Substituted benzopyrans as selective estrogen receptor-beta agonists

ABSTRACT

The present invention relates to substituted benzopyran derivatives, stereoisomers, and pharmaceutical acceptable salts thereof useful as Estrogen Receptor beta agonists for treating Estrogen Receptor beta mediated diseases such as benign prostatic hyperplasia.

BACKGROUND OF THE INVENTION

The present invention relates to novel cycloalkyl-benzopyrans andderivatives thereof, compositions containing those compounds, their useas selective estrogen receptor-beta agonists, and their use in thetreatment of estrogen receptor-beta mediated diseases such as prostatecancer, benign prostatic hyperplasia (hypertrophy), testicular cancer,ovarian cancer, lung cancer, cardiovascular diseases, neurodegenerativedisorders, urinary incontinence, central nervous system (CNS) disorders,gastrointestinal (GI) tract disorders, and osteoporosis.

Estrogens play important roles in the development and homeostasis of thereproductive, central nervous, skeletal, and cardiovascular systems ofboth males and females. Recently, a new ER isoform, ER-beta (also knownas ER-beta1) was cloned from a rat prostatic cDNA library and is presentin murine and human prostates. Consequently, the previous ER is nowdesignated as ER-alpha. ER-alpha and ER-beta share high amino acidhomology, have similar 17-3 Estradiol (E2) binding affinities, and canhetero- or homodimerize to form a signaling complex; Kuiper G G, et al.,Endocrinol. 138: 863-70 (1997); Kuiper G G et al., Proc. Natl. Acad.Sci. USA 93: 5925-30 (1996). Although E2 activates both ER-alpha andER-beta, ER-alpha stimulates transcription and cellular proliferation,while ER-beta suppresses ER-alpha activation. Interestingly, 3-beta,17-beta-androstanediol and 5-alpha-androstane have been proposed to beendogenous ligands for ER-beta; Weihua Z. et al. PNAS 98: 6330-5 (2001).3-Beta, 17-beta-androstanediol is a major metabolite ofdihydrotestosterone (DHT), the 5-alpha-reduced active intracellularandrogen in male accessory sex organs. ER-beta activation alsostimulates increased glutathione S-transferase and quinone reductaseexpression. These two enzymes have been shown to possess chemoprotectivedetoxification properties; Chang W Y et al., Prostate 40: 115-24 (1999);Montano M M et al., J. Biol. Chem. 273: 25443-9 (1998).

With the recent identification of ER-beta, and the recognition thatER-alpha and ER-beta have different biological roles, ER-selectivemodulators would similarly possess significant clinical utility. SinceER-beta is strongly expressed in a number of tissues including prostate,bladder, ovary, testis, lung, small intestine, vascular endothelium, andvarious parts of the brain, compounds that selectively modulate ER-betawould be of clinical importance in the treatment of a variety of diseaseconditions, such as prostate cancer, testicular cancer, ovarian cancer,lung cancer, cardiovascular diseases, neurodegenerative disorders,urinary incontinence, CNS disorders, GI tract disorders, andosteoporosis. Such compounds would have minimal effect on tissues thatcontain ER-alpha, and thus exhibit different side-effect profiles. Thus,ER-beta agonists will display different therapeutic profiles compared toER-alpha antagonists or agonists, and would be preferentially beneficialin tissues relying on ER-beta signaling.

The prostate gland produces components that are found in the semen andblood. Some of these are regulatory peptides. The prostate gland.comprises stroma and epithelium cells, the latter group consisting ofcolumnar secretory cells and basal non-secretory cells. Theproliferation of these basal cells, as well as stroma cells gives riseto benign prostatic hyperplasia (BPH), which is one common prostatedisease. BPH is a progressive condition that is characterized by thenodular enlargement of the prostatic tissue resulting in obstruction ofthe urethra. This results in increased frequency of urination, noncuria,poor urine stream, and hesitation or delay in starting the urine flow.Consequences of BPH can include hypertrophy of bladder smooth muscle,decompensated bladder, and increased incidence of urinary tractinfection. The development of BPH is considered to be an inescapablephenomenon for the aging male population. BPH is observed inapproximately 70% of males over the age of 70. Drug treatment for BPHcurrently employs alpha andrenergic antagonists for symptomatic reliefor steroid 5-alpha reductase inhibitors to reduce hyperplastic tissuebulk. These approaches are of limited therapeutic benefit.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to novel benzopyran derivatives of formula(I):

wherein

-   -   G is CHC₁-C₆ alkyl, C═O, CHOH, CF₂, C(OH)CF₃, CHCF₃, CH(OH)C₁-C₆        alkyl, CH—OC₁-C₆ alkyl, CH—O(CO)C₁-C₆alkyl, CHF, CHCN,        CBHC₂-C₄alkenyl, CHC₂-C₄alkynyl, CHbenzyl, difluoromethylene, O,        S(O)n, wherein n is 0-2;        including their enantiomers.        Another embodiment of the invention is a compound of formula II:

wherein

wherein C is CHC₁-C₆ alkyl, C═O, CHOH, CF₂, C(OH)CF₃, CHCF₃,CH(OH)C₁-C₆alkyl, CH—OC₁-C₆alkyl, CH—O(CO)C₁-C₆alkyl, CHF, O, S(O)n,wherein n is 0-2;

including the enantiomers;and the pharmaceutically acceptable salts thereof.

Compounds of the invention include the following, which should not beconstrued as in any way limiting the compounds included in theinvention:

-   a)    (2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9h-hexahydro-cyclopenta[c]chromen-8-ol;-   b)    (2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   c)    (2R,3aR,4S,9bS)-2-tert-Butyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   d)    (2S,3aS,4R,9bR)-2-tert-Butyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   e)    (3aS,4S,9bS)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol;-   f)    (3aR,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol;-   g)    (3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol;-   h)    (3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol;-   i)    (2S,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cyclopenta[a]naphthalen-8-ol;-   j)    (2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cyelopenta[a]naphthalen-8-ol;-   k)    (3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2μ⁶-thia-cyclopenta[a]naphthalen-8-ol;-   l)    (3aS,4R,9bR)-4-(4-Hydroxy-phenyl-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁶-thia-cyclopenta[a]naphthalen-8-ol;-   m)    (3aR,4S,9bS)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one;-   n)    (3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one;-   o)    (2S,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2,8-diol;-   p)    (2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2,8-diol;-   q)    (3aR,4S,9bS)-2,2-Difluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   r)    (3aS,4R,9bR)-2,2-Difluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   s)    (2S,3aR,4S,9bS)-4-(4Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   t)    (2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   u)    (2R,3aS,4S,9bS)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   v)    (2S,3a,4R,9bR)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   w)    (2R,3aR,4R,9bS)-2-Ethyl-4-h(4-hydroxy-phenyl)-1,2,3,3a,4,9bR-hexahydro-cyclopenta[c]chromene-2,8-diol;-   x)    (2S,3aS,4R,9bR)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9bR-hexahydro-cyclopenta[c]chromene-2,8-diol;-   y)    (2S,3aS,4R,9bR)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   z)    (2S,3aR,4S,9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   aa)    (2S,3aR,4S,9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   bb)    (2R,3aR,4S,9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   cc)    (2S,3aS,4R,9bR)-4-(4-Hydroxy-1-phenyl)-2-methoxy-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   dd)    (2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-methoxy-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   ee) (2S,3aS,4R,9bR)-Acetic acid    8-hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-yl    ester;-   ff) (2R,3aR,4S,9bS)-Acetic acid    8-hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-yl    ester;-   gg)    (2R,3aS,4R,9bR)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   hh)    (2S,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   ii)    (2S,3aS,4R,9bR)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   jj)    (2R,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   kk) (2R,3aR,4S,9bS)- and    (2S,3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2-carbonitrile;-   ll) (2S,3aR,4S,9bS)- and    (2R,3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydarocyclopenta[c]chromene-2-carbonitrile;-   mm) (3aR,4S,9bS)- and    (3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methylene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   nn) (3aR,4S,9bS)- and    (3aS,4R,9bR)-2-Difluoromethylene-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   oo) (3aR,4S,9bS)- and    (3aS,4R,9bR)-2-Ethynyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   pp)    2-Butyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexylydro-cyclopenta[c]chromen-8-ol;-   qq)    4-(4-Hydroxy-phenyl)-2-propyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   rr)    2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;-   ss)    2-Benzyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol;    including the enantiomers thereof.

The present invention also relates to novel benzopyran derivatives offormula (II):

wherein:

G and G′ are CH₂, C═O, C═CH₂, CHC₁-C₆ alkyl or CF₂, with the provisothat when G′ is other than CH₂, G must be CH₂ and that when G is otherthan CH₂, G′ must be CH₂;

including the enantiomers thereof; and the pharmaceutically acceptablesalts thereof.

Compounds of the invention include the following, which should not beconstrued as in any way limiting the compounds included in theinvention:

-   a)    (6S,6aR,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6,6a,7,8,10,10a-hexahydro-benzo[c]chromen-9-one;-   b)    (6aR,6,S,10aS)-6-(4-Hydroxy-phenyl)-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol;-   c)    (6aR,6S,9S,10aS)-6-(4-Hydroxy-phenyl)-9-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol;-   d)    (6aR,6S,9R,10aS)-6-(4-Hydroxy-phenyl)-9-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol;-   e)    (6aR,6S,10aS)-9,9-Difluoro-6-(4-hydroxy-phenyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol;-   f)    (6aR,6S,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6a,9,10,10a-tetrahydro-6H,7;    H-benzo[c]chromen-8-one;    including the enantiomers and the pharmaceutically acceptable salts    thereof.

In a second embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) and a pharmaceutically acceptable carrier.

In a further embodiment, the present invention provides medical methodsof employing compounds formula (I) as agonists of estrogen receptor(“ER”) beta, further utilized for the treatment of ER beta-mediateddiseases such as prostate cancer, benign prostatic hyperplasia,testicular cancer, cardiovascular diseases, neurodegenerative disorders,urinary incontinence, central nervous system (CNS) disorders,gastrointestinal (GI) tract disorders, and osteoporosis.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application:

a) the term “C₁-C₆ alkyl” refers to a branched or straight chained alkylradical containing from 1 to 6 carbon atoms, such as methyl (Me), ethyl(Et), n-propyl, isopropyl, n-butyl, isobutyl, sec butyl (s-Bu),tert-butyl (t-Bu), pentyl, hexyl, etc.;

b) the term “C₂-C₄ alkenyl” refers to a straight or branched

hydrocarbon chain of 2 to 4 carbon atoms with at least one carbon-carbondouble bond. Examples of C₂-C₄ alkenyl groups include, but are notlimited to, ethenyl(vinyl), propen-1-yl, propen-2-yl(isoprenyl),propen-3-yl(allyl), 2-methyl-propen-3-yl, 2-buten-4-yl,2-methyl-propen-1-yl, and 1-buten-1-yl;

c) the term “C₂-C₄ alkynyl” refers to a straight or branched

hydrocarbon chain of 2 to 4 carbon atoms with at least one carbon-carbontriple bond. Examples of C₂-C₄ alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl(isoprynyl), propyn-3-yl,2-methyl-propyn-3-yl, 2-butyn-4-yl, 2-methyl-propyn-1-yl, and1-butyn-1-yl;

d) the term “halide” refers to a fluorine atom, chlorine atom, bromineatom, or iodine atom;

e) the designation

refers to a bond for which the stereochemistry is not designated:

f) the designation

refers to a bond that protrudes forward out of the plane of the page;

g) the designation

refers to a bond that protrudes backward out of the plane of the page;

h) as used in the preparations and examples the following terms have theindicated meanings; “ng” refers to nanograms; “μg” refers to micrograms;“mg” refers to milligrams; “g” refers to grams; “kg” refers tokilograms; “nmole” refers to nanomoles; “mmol” refers to millimoles;“mol” refers to moles; “μL” refers to microliters; “mL” refers tomilliliters; “L” refers to liters; “R_(f)” refers to retention factor;“° C.” refers to degrees Celsius; “bp” refers to boiling point; “mm ofHg” refers to pressure in millimeters of mercury; “mp” refers to meltingpoint; “dec” refers to decomposition; “[α]² _(D) ⁰” refer to specificrotation of the D line of sodium at 20° C. obtained in a 1. decimetercell; “c” refers to concentration in g/mL; “nM” refers to nanomolar;“μM” refers to micromolar; “mM” refers to millimolar; “M” refers tomolar; “K_(i)” refers to inhibition constant; “K_(d)” refers todissociation constant; “psi” refers to pounds per square inch; “rpm”refers to revolutions per minute; “HPLC” refers to high performanceliquid chromatography; “HRMS” refers to high resolution mass spectrum;“THF” refers to tetrahydrofuran; “brine” refers to a saturated aqueoussolution of sodium chloride; “L.O.D.” refers to loss on drying; “μCi”refers to microcuries; “i.p.” refers to intraperitoneally; “i.v.” refersto intravenously; and “DPM” refers to disintegrations per minute;

i) the term “enantiomeric excess” or “ee” refers to the percent by whichone enantiomer, E1, is in excess in a mixture of the two enantiomers, E1plus E2, such that (E1−E2)+(E1+E2))×100=ee;

The compounds used in the method of the present invention may have oneor more asymmetric centers. As a consequence of these chiral centers,the compounds of the present invention occur as racemates and asindividual enantiomers, as well as diastereomers and mixtures ofdiastereomers. All asymmetric forms, individual isomers and combinationsthereof, are within the scope of the present invention.

In order to preferentially prepare one optical isomer over itsenantiomer, a number of routes are available. As an example, a mixtureof enantiomers may be prepared, and then the two enantiomers may beseparated. A commonly employed method for the separation of a racemicmixture is the use of chiral high pressure liquid chromatography.Further details regarding resolution of enantiomeric mixtures may befound in J. Jacques, et al, Enantiomers, Racemates, and Resolutions,(1991).

The term “pharmaceutically acceptable salts thereof” refers to either,an acid addition salt or a basic addition salt.

The expression. “pharmaceutically acceptable acid addition salts” isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by formula (I). Illustrativeinorganic acids that form suitable salts include hydrochloric,hydrobromic, sulphuric, and phosphoric acid and acid metal salts such assodium monohydrogen orthophosphate, and potassium hydrogen sulfate.Illustrative organic acids that form suitable salts include the mono-,di-, and tricarboxylic acids. Illustrative of such acids are forexample, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic,benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic,2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such asbenzenesulfonic acid, methanesulfonic acid, and 2-hydroxyethanesulfonicacid. Such salts can exist in either a hydrated or substantiallyanhydrous form. In general, the acid addition salts of these compoundsare soluble in water and various hydrophilic organic solvents, and whichin comparison to their free base forms, generally demonstrate highermelting points.

The expression “pharmaceutically acceptable basic addition salts” isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by formula (I). Illustrative baseswhich form suitable salts include alkali metal or alkaline-earth metalhydroxides such as sodium, potassium, calcium, magnesium, or bariumhydroxides; ammonia, and aliphatic, alicyclic, or aromatic organicamines such as methylamine, dimethylamine, trimethylamine, and picoline.Either the mono- or di-basic salts can be formed with those compounds.

Illustrative examples of the compounds encompassed by the presentinvention include the racemic mixtures and specific enantiomers of thefollowing compounds:

Reaction Schemes

Compounds of formula (I) and intermediates thereof can be prepared asdescribed in Reaction Schemes A-I below. All substituents, unlessotherwise indicated, are previously defined. The reagents and stalingmaterials are readily available to one of ordinary skill in the art.

In scheme A, alkyl substituted 2-oxocyclopentanecarboxylates 2, whereinis CHMe or CHt-Bu, were prepared using a Dieckman cyclization of thealkyl substituted adipic acids 1, which are commercially available. To aheated solution of an appropriate base, such as NaOMe (sodium methoxide)in an appropriate solvent, such as toluene, an appropriate amount of Iis added to give the corresponding 2-oxocyclopentanecarboxylates 2. Theproduct of formula 2 can be isolated and purified by techniques wellknown in the art.

The 2-oxocyclopentanecarboxylates 2 are then reacted with an appropriateamount of trifluoromethanesulfonic (triflic) anhydride (Tf₂O) in thepresence of an appropriate base, as would be known to one skilled in theart, such as 2,6-di-tert-butyl-4-methyl-pyridine or diisopropyl ethylamine (iPr₂NEt), to form the triflates 3, wherein G is CHMe or CHt-Bu(tertiary-butyl). The reaction may be carried out at room temperatureand the product 3 isolated and purified by methods well known in theart.

In scheme B, heterocycles 4, wherein G is either O or S, were preparedby Michael addition of methyl glycolate or methyl thioglycolate tomethyl acrylate followed by Dieckmann cyclization in one pot. The methylglycolate or methyl thioglycolate is added to a suspension of anappropriate base, preferably a metal hydride, such as sodium hydride(NaH) in ether and stirred until the evolution of H₂ gas ceases in thecase of methyl glycolate or NaOMe in methanol, in the case of methylthioglycolate. The residue is concentrated and dissolved in DMSO,cooled, and then methyl acrylate is added drop wise. The reactionmixture is then warmed to room temperature and stirred. The product 4 isthen extracted and purified by methods well known in the art. Theresulting heterocycles 4 are then reacted with Tf₂ O in the presence ofan appropriate base to form triflates 3, wherein G is oxygen (O) orsulfur (S).

In scheme C, hydroquinone 5 is protected as the bis-metoxymethyl (MOM)ether using sodium hydride and chloromethyl methyl ether (MOMCl). Ortholithiation of protected hydroquinone 6 may be accomplished withsec-butyllithium (sBuLi) followed by quenching with triisopropyl borateto form the boronic acid 7. Boronic acid 7 was coupled with triflates 3using Suzuki conditions, using the reagentstetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), lithium chloride(LiCl), sodium carbonate (Na₂ CO₃), water and dimethoxyethane (DME)(Miyaura, N.; Suzuki, A; Chem. Rev. 1995, 95, 2457-2483) to giveunsaturated esters 8, wherein G is either CHMe, CHt-Bu, O or S.

In scheme D, the unsaturated esters 8 as prepared in scheme C arehydrogenated over Palladium on carbon (PdfC) and then transformed intoWeinreb amides 9, using isopropyl-magnesium chloride (iPr-MgCl) andN,O-dimethylhydroxylamine-HCl (HN(OMe)Me). The Weinreb amides 9 are thenreacted with lithiated p-bromophenyl methoxymethyl ether in anappropriate solvent such as tetrahydrofuran (THF) to give thecorresponding ketones 10. Deprotection and cyclization of ketones 10under acidic conditions para-toluenesulfonic acid (p-TsOH) in methanolis followed by reduction in the same pot with sodium cyanoborohydride(NaBH₃CN). The reduction is kept acidic by addition of HCl which givesbenzopyrans 11, wherein G is CHMe, CHt-Bu, O or S.

In scheme E, the tetrahydrothiophene 12, as prepared in scheme D (11d)may be oxidized to the sulfoxide 13 with potassium peroxymonosulfate(oxone) in MeOH and water at room temperature. The sulfone 14 isprepared from the tetrahydrothiophene 12 using the same conditions withheating at 50° and longer reaction times.

In scheme F, 2,5-dimethoxycinnamic acid 15 is treated with borontribromide (BBr₃) to form 6-hydroxycoumarin 16. 6-Hydroxycoumarin 16 canbe protected as the bis-methoxymethyl ether (MOM) 17a usingN,N-diisopropylethylamine (iPr₂NEt) and MOMCl or as the benzyl ether(Bn) 17b using cesium carbonate (CsCO₃) and benzyl bromide (BnBr).

In scheme G, the cyclopentanoid 18 is formed via [3+2] cycloaddition to6-methoxymethoxy coumarin 17a using Trost's trimethylenemethanechemistry by using 2-(acetyoxymethly)allyl-triethylsilane, palladiumacetate (Pd(OAc)₂) and triisopropyl phosphite (P(OiPr)₃) (Trost, B. M.Angew. Chem. Int. Ed. Engl. 1986, 25, 1-20). The exomethylene of 0.8 isdihydroxylated using osmium tetroxide (OsO₄) and N-methylmorpholineN-oxide followed by protection of the diol using phosgene (Cl₂ CO) togive the cyclic carbonate 19. The enol triflate 20 is then formed bydeprotonating 19 with an appropriate base, as known by one skilled inthe art, such as lithium bis(trimethylsilyl)amide (LHMDS) followed bytrapping the enolate with N-phenyltrifluoromethanesulfonimide (PhNTf₂)in the presence of hexamethylphosphoramide [HMPA]in an appropriatesolvent, such as THF. The enol triflate 20 was coupled with lithiatedp-bromophenyl methoxymethyl ether using Negishi conditions using zincchloride (ZnCl₂), Pd(PPh₃)₄, in an appropriate solvent, such as THF(Negishi, E. Acc. Chem. Res. 1982, 15, 340-348) to give flavene 21. Theenol of flavene 21 is reduced with hydrogen over Pd/C in an anappropriate solvent such as THF and methanol to give flavan 22. Thecarbonate of flavan 22 is then hydrolyzed with an appropriate base, suchas lithium hydroxide (LiOH), followed by oxidative cleavage of the diolwith an appropriate oxidant such as sodium periodate (NaIO₄) in one potto give the cyclopentanone 23. The methoxymethyl protecting groups of 23could then be removed using appropriate acidic conditions such as 3 MHCl in THF to give the cyclopentanone 24, wherein G is C═O.

In scheme 11, cyclopentanone :23 may be reduced with an appropriatereductant, such as sodium borohydride (NaBH₄), to give alcohol 25 as asingle diastereomer which is then deprotected, as described above inscheme G, to give alcohol 26, wherein G is CHOH. Alcohol 25 was invertedusing Mitsunobu conditions, using benzoic acid, diethyl azodicarboxylate(DEAD), triphenylphosphine (PPh) (Mitsunobu, O. Synthesis, 1981, 1-28.),followed by hydrolysis of the benzoate with an appropriate base, suchas, lithium hydroxide (LiOH), to give alcohol 27, wherein G is CHOH.Cyclopentanone 23 is treated with (diethylamino)sulfur trifluoride(DAST) to give difluorocyclopentane 29 which is deprotected under acidconditions, such as HCl in THF, to give difluorocyclopentane 30, whereinG is CF₂. Cyclopentanone 23 is reacted with(trifluoromethyl)trimethylsilane (TMSCF₃) in the presence of tetra-butylammonium fluoride (TBAF) to give alcohol 31. Radical deoxygenation of 31is accomplished via the methyl oxalyl ester (formed using methylchloroglyoxylate (CICOCO₂e), DMAP, and Et₃ N), using triphenyltinhydride (Bu₃ Sn1H) and 2,2′-Azobisisobutlyronitrile (AIBN) as describedby Dolan (Dolan, S.C.; MacMillan, J. J. Chem. Soc., Chem. Commun. 1985,1588-1589) to give trifluoromethyls 32 and 33 as a separable mixture ofdiastereomers. The diastereomers are then separately deprotected, underacidic conditions, such as 1HCl in THF, to give trifluoromethyls 34 and35, wherein G is CHCF₃. Cyclopenanone 23 was reacted with Grignardreagents (R¹MgBr, for example) in the presence of cerium trichloride(CeCl₃) to give alcohols 36 which are deprotected under acidicconditions, such as HCl in THF, to give alcohols 37. Radicaldeoxygenation of 36 was accomplished as described above for 31 to givealkyl substituted cyclopentanes 38 which are deprotected to give alkylcyclopentanes 39, wherein G is CHEt (ethyl). One skilled in the artwould know how to make other equivalent benzopyrans wherein G isCH(C₁-C₆) lower alkyl, by the appropriate Grignard reagent.

Alcohol 25 may also be reacted with alkyl halides, such as methyl iodide(R′X), to give alkyl ethers 40, which are then deprotected, under acidicconditions, such as HCl in THF, to give alkyl ethers 41, wherein G isCHOR′, wherein R′ is (C₁-C₆) lower alkyl. Alcohols 25 may also bereacted with any appropriate alkyl acyl chloride or alkyl acylanhydride, such as acetic anhydride (R′X), in the presense of anappropriate base and an appropriate acylation catalyst, such asdimethylaminopyridine (DMAP) to give alkyl esters 42 which aredeprotected, under acidic conditions, to give alkyl esters 43, wherein Gis CHOR′, wherein R′ is defined as above. Alcohols 25 may also bereacted with (diethylamino)sulfur trifluoride (DAST) to givefluorocyclopentanes 44 which is deprotected, under acidic conditions, togive fluorocyclopentanes 45, Wherein G is CHF. In the same way asdescribed above alcohol 27 may be converted into the correspondingdiastereomer such as fluorocyclopentane 47, wherein C is CHF.

Compounds of formula (II) and intermediates thereof can be prepared asdescribed in Reaction Schemes J-O below. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

Beginning with the known hydroxy-coumarin 1 (Cramer, Chem Ber. 1956, 89,354), protection of the phenol as its benzyl ether using an appropriatemetal hydride, such as sodium hydride (NaH) with an appropriatebenzylating agent such as benzyl bromide (BnBr), as would be known byone skilled in the art, provides coumarin 2. Diels-Alder reaction with2-trimethylsilyloxy-1,3-butadiene in solvent such as ortho-xylene, at atemperature of approximately 130° C., followed by workup of the reactionin a desilylating agent, such as tetrabutylammonium fluoride (TBAF),provides the desired cycloaddition product 3. A two-step decarboxylationprovides keto-lactone 4, by first treating compound 3 with a hydroxidesource, such as lithium hydroxide (LiOH) in an appropriate solventmixture, such at tetrahydrofuran (THF), ethanol and water, followed byrefluxing of the intermediate carboxylic acid in an appropriate solvent, such as xylenes. Ketone 4 is selectively protected as it cyclic acetal5, by treating ketone 4 with the protecting agent ethylene glycol(HO(CH₂)₂OH), in the presence of a suitable acid, such as para-toluenesulfonic acid (TsOH) in a suitable solvent, such as toluene, using aDean-Stark apparatus, as is known by one skilled in the art, Treatmentof the lactone 5 with a suitable base, such as potassiumhexamethyldisilazane (KHMDS) in the presence of stoichiometrichexamethylphosphoramide (HMPA), followed by quenching of the enolatewith a suitable triflating source such as N-phenyl triflamide (PhNTf₂)provides the intermediate enol triflate 6 as a clear solid. Suzukicross-coupling of 6 with parabenzyloxyphenylboronic acid, in thepresence of chloride salt, such as lithium chloride (LiCl), and asuitable base, such as sodium carborate (Na₂ CO₃), using a metalcatalyst such as palladium-tetrakis triphenylphosphine (Pd(PPh₃)₄) in asuitable solvent, such as ethylene glycol dimethyl ether (DME) providesthe enol ether 7 under reflux. Hydrogenation of the benzyl ethers andthe alkene of 7 using a metal catalyst, such palladium on carbon (Pd-C)in a protic solvent, such as methanol under a hydrogen atmosphere,affords diphenol 8. This step is followed by acid-promoted cleavage ofthe ketal protecting group, using an acid such as HCl in an appropriatesolvent, such as THF/H₂O, affords the desired ketone 9 in good yield.

Analogues of 9 are generated in the schemes K-M. In scheme K, sodiumborohydride (NaBH₄) reduction of the ketone 9, in a suitable proticsolvent, such as ethanol, provides an approximately 2:1 ratio of epimers10 and 11.

Furthermore in scheme L, protection of 9 as itsbis-tertbutyldimethylsilyl ether (TBS) using an appropriate silylatingagent, such as tertbutyldimethylsilyl chloride (TBS-Cl) in the presenceof an appropriate base, such as imidazole, provides bis-silyl ether 12.Alternatively, protection of 9 as its bis-methoxymethyl ether (MOM) 13,using an appropriate protecting agent such methoxymethyl chloride(MOM-Cl), in the presence of an appropriate base, such as potassiumtert-butoxide (KOtBu), in an appropriate solvent, such asdimethylformamide (DMF) provides bis-ether 13,

Bis silyl ether 12 is treated with the Tebbe reagent (Cp₂TiCl(H)Me), inthe presence of pyridine base, in an appropriate solvent, such as THF,at a temperature range of −35-50° C., affords the alkenylated product14. Desilylation with an appropriate fluoride source. such as TBAF, withan appropriate solvent, such as TH-IF, provides exo-methylene 15, whichis then hydrogenated with a suitable metal catalyst, such as Pd—C, in anappropriate protic solvent, such as methanol, under an atmosphere ofhydrogen, to provide an approximately 1:1 mixture of inseparablemethylated product 16.

In scheme N, treatment of the bis-MOM ether 13 from scheme K, with afluorinating source, such as (diethylamino) sulfur trifluoride (DAST) at45° C., in a suitable chlorinated solvent, such as 1,2-dichloroethane(1,2-DCE), affords the gem-difluoro intermediate 17. Removal of the MOMprotecting groups is carried out with a suitable acid, such HCl, in anappropriate solvent mixture, such as THF, in the presence of wateraffords the desired difluoride 18.

In scheme O, the synthesis of isomeric ketone 27 is carried out in themanner described below. Allyl-Grignard addition, using an appropriateallyl-Grignard reagent, such as allyl-magnesium bromide at lowtemperature, such as 0° C., in a suitable ethereal solvent, such as THF,to the aforementioned coumarin 2, from scheme J, in a 1,4 sense providesthe β-keto ester 19. Decarboxylation of 19 to 20 occurs under identicalconditions as the conversion of 3 to 4 as described in scheme anappropriate base, such as KHMDS, in the presence of HMPA, followed byreaction of the enolate with an appropriate allylating reagent, such as2-methoxymethyl-allyl iodide provides allylated 21. Ring closingmetathesis of 21 using an appropriate Grubbs reagent a, such as[1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-tricyclohexylphosphine)ruthenium],in a suitable chlorinated solvent, such as methylene chloride (CH₂Cl₂),at a concentration of 0.01 M at reflux, affords the cyclic enol-ether22. Hydrolysis of the enol ether, using an appropriate acid, such asHCl, in an ethereal solvent, such as THF containing water provides theintermediate ketone, which is converted to ketal 23 under identicalconditions as described above for the conversion of 4 to 5 in scheme K.Conversion of the ketal 23 to final ketone 27 identically follows theconversion of ketal 5 to ketone 9 as described in scheme J.

In Scheme P, an alternative synthesis of cyclopentanone 24 with benzylprotecting groups on the phenols is described. The cyclopentanoid 48 isformed via [3+2]cycloaddition to 8-benzyloxy coumarin 17b using Trost'strimethylenemethane chemistry using2-(acetyoxymethyl)allyl-triethylsilane, palladium acetate (Pd(OAc)₂) andtriisopropyl phosphite (P(OiPr)s) (Trost, B. M. Angew. Chem. Int. Ed.Engl. 1986, 25, 1-20). The enol triflate 49 is then formed bydeprotonating 48 with an appropriate base, as known by one skilled inthe art, such as potassium bis(trimethylsilyl)amide (KHMDS) followed bytrapping the enolate with an appropriate triflating agent such asA-phenyltrifluoromethanesulfonimide (PhNTf₂) in an appropriate solvent,such as THE. The enol triflate 49 can be coupled using Negishiconditions with the aryl zinc derived from p-bromophenylbenzyl ether, anappropriate palladium catalyst such as Pd(PPh₃)₄, in an appropriatesolvent, such as THF (Negishi, E. Acc. Chem. Res. 1982, 15, 340-348) togive flavene 50. The enol of flavene 50 is reduced with triethylsilane(Et₃ SiH) in the presence of trifluoroacetic acid (TFA) in methylenechloride to give flavan 51. The exomethylene of 51 is dihydroxylatedusing osmium tetroxide (OsO₄) and N-methylmorpholine-A-oxide (NMO)followed by oxidative cleavage of the di1 with an appropriate oxidantsuch as sodium periodate (NaIO₄) in one pot to give the cyclopentanone52.

In Scheme Q, cyclopentanone 52 is converted into two nitrile substituteddiastereomers. The ketone of cyclopentanone 52 can be reduced with aappropriate hydride reagent such as sodium borohydride (NaBH₄) followedby displacement of the resulting alcohol with cyanide using acetonecyanohydrin under appropriate Mitsunobu conditions (Mitsunobu, O,Synthesis 1981, 1-28) to afford nitrile 53. Nitrile 53 is deprotectedusing appropriate hydrogenation. conditions such as 10% palladium oncarbon (Pd/C) and hydrogen (H₂) to give deprotected nitrile 54. Toobtain the opposite diastereomer, the ketone of cyclopentanone 52 isreduced to the alcohol as described above and then inverted usingp-nitrobenzoic acid under appropriate Mitsunobu conditions followed byhydrolysis of the benzoate using lithium hydroxide (LiOH) followed bydisplacement of the resulting alcohol with cyanide as described above toafford nitrile 55. Nitrile 55 is deprotected using appropriatehydrogenation conditions as described above to give deprotected nitrile56.

In scheme R, the benzyl protecting groups of cyclopentanone 52 areexchanged for silyl protecting groups. The benzyl protecting groups areremoved using appropriate hydrogenation conditions such as 10% palladiumon carbon (Pd/C) and hydrogen (H₂) followed by reaction withtri-tert-butylsilyl chloride (TBSCI), catalyticN,N-dimethylaminopyrindine (DMAP), and imidazole in dimethylformamide(DMF) to give silyl protected cyclopentanone 57. Silyl protectedcyclopentanone 57 is reacted with the phosphonium ylide prepared frommethyltriphenylphosphonium bromide and potassium hexamethyldisilazane(KHMDS) to give alkene 58. Alkene 58 is deprotected usingtetrabutylammonium fluoride (TBAF) to afford deprotected alkene 59.Silyl protected cyclopentanone 57 is reacted with the lithium anion of(Difluoromethyl)diphenylphosphine oxide using the conditions describedby Edwards et al. (Edwards, M. L; Stemerick, D. M.; Jarvi, E. T.;Matthews, D. P.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5571-5574)to give difluoromethylene 60. Difluoromethylene 60 can be deprotectedusing TBAF to give deprotected difluoromethylene 61.

In Scheme S, cyclopentanone 57 is reacted with the organocerium reagentformed by lithiating trimethylsilylacetylene with n-butyllithiumfollowed by reaction with cerium trichloride to give an alcohol. Radicaldeoxygenation of the alcohol is accomplished via the methyl oxalyl ester(formed using methyl chloroglyoxylate (CICOCO₂Me), DMAP, and Et₃N),using phenyltin hydride (Ph₃ SnH) and 2,2′-Azobisisobutyronitrile (AIBN)as described by Dolan et al. (Dolan, S. C.; MacMillan, J. J. Chem. Soc.;Chem. Commun. 1985, 1588-1589) to give alkyne 62 as a 5:1 mixture ofdiastereomers. Alkyne 62 was deprotected with TBAF to give deprotectedalkyne 63 as a 5:1 mixture of diastereomers.

In Scheme T, cyclopentanone 52 is reacted with a series of phosphoniumylide reagents generated from alkyl or benzyl triphenyl-phosphoniumhalides (RPPh₃ X) such as ethyltriphenylphosphonium bromide (EtPPh₃Br)using an appropriate base such as potassium hexamethyldisilazane (KHMDS)to give alkenes 64. The alkenes can be reduced and the benzyl protectinggroups removed in the same reaction using appropriate hydrogenationconditions such as 10% palladium on carbon (Pd/C) and hydrogen (H₂) togive deprotected alkenes 65.

Preparation 1 1,4-Bis-methoxymethoxy-benzene (6)

Stir a suspension of sodium hydride (60% in mineral oil, 3.81 g, 95.45mmol) in anhydrous DMF (50 mL) under nitrogen atmosphere at 0° C. andadd a solution of hydroquinone (5.00 g, 45.45 mmol) in anhydrous DMF (50mL) dropwise. Add to this suspension methoxymethyl chloride (7.2 mL,95.45 mmol) dropwise with additional gas evolution noted. Allow thereaction to warm to ambient temperature and stir for one hour. Quenchthe reaction with water and add diethyl ether. Wash the organic layerwith 1N sodium hydroxide and brine. Dry the organic layer over sodiumsulfate, concentrate in vacuo, and flash chromatograph with 20% ethylacetate/hexane to yield 1,4-bis-methoxymethoxy-benzene 6 (5.64 g, 63%)as a clear oil. ¹H NMR (CDCl₃): 6.97 (s, 4H), 5.11 (s, 4H), 3.47 (s,6H).

Preparation 2 2,5-Bis-methoxymethoxy phenylboronic acid (7)

Cool a solution of 1,4-bis-methoxymethoxy-benzene 5 (1.2.0 g, 60.6 mmol)in dry THF (250 mL) to −78° C. Add s-BuLi (1.3 M in hexane, 51 mL, 66.6mmol) dropwise. Stir the reaction for 15 minutes and then addtriisopropyl borate (14.2 mL, 60.6 mmol) slowly. Stir the reaction at−78° C. for 1 hour and warm to room temperature. Quench the reactionwith 10% HCl and stir for 10 minutes. Extract with EtOAc (2×). Drycombined organic extracts (Na₂SO₄), filter, and concentrate in vacuo.Purify by flash chromatography (250 g SiO₂, 20-50% EtOAc/hexanes andthen 50% EtOAc/hexanes) to give 2,5-Bis-methoxymethoxy phenylboronicacid 7 (9.73 g, 40.2 mmol, 66%) as a yellow solid. ¹H NMR (δ, 400 MHz,CDCl₃): 7.50 (d, J=2.0 Hz, 1H), 7.09-7.07 (m, 2H), 5.93 (s, 2H), 5.24(s, 2H), 5.14 (s, 2H), 3.49 (s, 3H), 3.48 (s, 3H). LRMS calcd, forC₁₀H₁₄ BO₆: 241.0; found (electrospray, M−1) 241.0.

Preparation 3 (R)-3-Methyl-hexanedioic acid dimethyl ester (1a)

Dissolve (R)-(+)-3-methyladipic acid (5.0 g, 31.2 mmol) in MeOH (317 mL)and add concentrated H₂SO₄ (17 mL, 312 mmol). Heat the reaction to 60°C. and stir overnight. Cool the reaction to 0° C. and neutralize withaqueous NaOH. Concentrate the mixture to half the volume and dilute withEtOAc. Separate and extract the aqueous solution with EtOAc (2×).Combine the organic solutions and wash with saturated aqueous NaHCO₃ andbrine. Dry the organic layer (Na₂SO₄), filter and concentrate in vacuoto yield (R)-3-Methyl-hexanedioic acid dimethyl ester 1a as a colorlessliquid (5.53 g, 29.3 mmol, 94%), 94% which is used without furtherpurification. ¹H NMR (δ, 400 MHz, CDCl₃): 3.67 (s, 6H), 2.41-2.27 (min,3H), 21.6 (dd, J=7.9, 14.9 Hz, 1H), 1.99 (octet, J=6.6 Hz, 1H),1.75-1.49 (m, 2H), 0.96 (d, J=7.0 Hz, 3H). MS (EI, M-2Me, M-CO₂ Me):158, 128.

Preparation 4 (R)-4-Methyl-2-oxo-cyclopentanecearboxylic acid methylester (2a)

Prepare a solution of NaOMe (3.14 g, 58.3 mmol) in MeOH (9.2 mL), Addtoluene (40 mL) and heat to 70° C. Add a solution of(R)-3-methyl-hexanedioic acid dimethyl ester 1a (5.4 g, 29.1 mmol) intoluene (18 mL). Attach a distillation apparatus and continue heating at75° C. After distillation of methanol is complete, heat the reaction to110° C. and stir for 2 hrs, Cool the reaction to room temperature,quench with 1.0 N HCl and extract with Et₂O (2×). Wash the combinedorganic extracts with saturated aqueous NaHCO₃. Dry the organic solution(MgSO₄), filter and concentrate in vacuo. Purify by flash chromatography(silica gel, 0-30% EtOAc/Hexane) to yield a 3:1 mixture of tworegioisomers (2.8 g, 24.3 mmol, 84%) as a pale yellow oil with the majorisomer being 4-methyl-2-oxo-cyclopentanecarboxylic acid methyl ester 2a,The material was used without further purification in the nextpreparation. HRMS calcd. 157.0864; found (electrospray, M+1): 157.0864.

Preparation 5(R)-4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylicacid methyl ester (3a)

Stir a solution of 4-methyl-2-oxo-cyclopentanecarboxylic acid methylester 2a (2.86 g, 17.9 mmol, 3:1 mixture of isomers) in anhydrousdichloromethane (120 mL) cooled to −78° C. and add diisopropylethylamine(12.1 mL, 71.6 mmol) and triflic anhydride (3.4 mL, 19.7 mmol). Stir thereaction for 16 hours, allowing it to warm to room temperature. Quenchthe reaction with water and wash with 10% citric acid followed by brine.Dry the organic layer over sodium sulfate, filter, and concentrate invacuo. Purify by flash chromatography (silica gel, 0-30% EtOAc/hexanesthen 30% EtOAc/h-exanes) to yield4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acidmethyl ester 3a (2.62 g, 9.1 mmol, 85%) as the major product which isused without further purification. The yield is based on the amount ofthe major isomer present in the staring material. ¹H NMR (δ, 400 MHz,CDCl₃): 3.79 (s. 3H), 2.96-2.82 (m, 2H), 2.56-2.44 (m, 1H), 2.41-2.27(m, 2H), 1.14 (d, 3H, J=7.0 Hz), MS calcd, 288.03; MS (EI, M+) 288.04.

Preparation 6(S)-2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylicacid methyl ester (8a)

Prepare a mixture of4-Methyl-2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acidmethyl ester 3a (2.5 g, 8.7 mmol), 2,5-Bis-methoxymethoxy phenylboronicacid 7 (2.31 g. 9.5 mmol), tetrakis(triphenylphosphine)palladium (485mg, 0.435 mmol), and LiCl (1.1 g, 26.1 mmol) in DME (80 mL). Add 2.0 Msolution of Na₂ CO₃ (10 mL, 21.7 mmol) and heat the reaction to refluxand stir for 2 hours. Cool the reaction to room temperature andpartitioned between CH₂Cl₂ and saturated aqueous NaHCO₃. Separate andextract the aqueous solution with CH₂Cl₂ (2×). Combine the organicextracts, dry (Na₂SO₄), filter and concentrate in vacuo. Purify by flashchromatography (125 g SiO₂, 0-30% EtOAc/hexane and 30% EtOAc/hexane) toafford2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylicacid methyl ester 8a (2.4 g, 7.1 mmol, 83%) as a yellow oil. ¹H NMR (δ,400 MHz, CDCl₃): 7.02 (d, 1H, J=9.2 Hz), 6.90 (dd, 11, J=9.2, 3.1 Hz),6.80 (d, 1H, J=3.1 Hz), 5.10 (s, 2H), 5.03 (s, 2H), 3.56 (s, 31-1), 3.48(s, 31H), 3.44 (s, 31-), 3.01-2.91 (m, 2H), 2.53-2.37 (m, 3-1), 1.14 (d,3H, J=6.6 Hz). HRMS calcd. 337.1651; found (electrospray, M+1) 337.1647.

Preparation 7(1S,2R,4S)-2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylicacid methyl ester

To a suspension of 10% palladium on carbon (0.5 g) in methanol (40 mL)add a solution of 2-(2,5-Bis-metoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester8a (2.4 g, 7.1 mmol) in methanol (10 mL). Place the mixture underhydrogen (60 psi) at 40° C. for twelve hours. Purge the reaction withnitrogen and filter through celite. Concentrate the filtrate in vacuo toyield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylicacid methyl ester (2.47 g, 7.1 mmol, 100%) as a clear oil. ¹H NMR (δ,400 MHz, CDCl₃): 6.98 (d, 1H, J=8.8 Hz), 6.85 (d, 1H, J=8.8), 6.81 (dd,1, J-3,H , 8.8 Hz), 5.15 (s, 21), 5.10 (d, 1H, J=6.6 Hz), 5.07 (d, J=6.6Hz), 3.77-3.67 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.38-3.31 (m, 1H),3.15 (s, 3H), 2.19-2.03 (m, 2H), 1.96-1.68 (m, 31), 1.19 (d, 31, J=6.2Hz). HRMS calcd. 339.1808; found (electrospray, M+1) 339.1818.

Preparation 8(1S,2R,4S)-2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylicacid methoxy-methyl-amide (9a)

Cool a suspension of2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acidmethyl ester (2.4 g. 7.1 mmol) and N,O-dimethylhydroxylaminehydrochloride (1.4 g, 14.2 mmol) in anhydrous THF (60 mL) to −10° C. inan NaCl/ice bath. Add isopropyl magnesium chloride (2.0 M in THF, 14.2mL, 28.4 mmol) and stir the reaction for 30 min. Quench the reactionwith saturated ammonium chloride. Add EtOAc and wash with brine. Dry theorganic solution. (Na₂SO₄), filter and concentrate in vacuo to yield2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acidmethoxy-methyl-amide 9a (2.5 g, 6.8 mmol, 96%) as a pale yellow oil. ¹HNMR (δ, 400 MHz, CDCl₃): 6.95 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=3.0 Hz),6.79 (dd, 1H, J=8.8, 3.0 Hz), 5.16-5.03 (m, 4H), 3.80 (m, 1H), 3.64 (m,1H), 3.50 (s, 3H), 3.46 (s, 3H), 3.4-3 (s, 3H), 2.74 (s, 3H); 2.13-2.05(m, 2H), 1.95-1.79 (m, 3H), 1.19 (d, 31H, J=6.2 Hz). HRMS calcd.368.2073; found (electrospray, M+1) 368.2065.

Preparation 9(1S,2R,4S)-[2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone(10a)

Cool a solution of 1-bromo-4-methoxymethoxy benzene (2.8 g, 13.0 mmol)in 100 mL of THF to −78° C. Add s-BuLi (20 mL of a 1.3 M solution inhexane, 26 mmol) drop wise. Stir the reaction for 20 min and thentransfer via cannula to a solution of2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acidmethoxy-methyl-amide 9a (2.4 g, 6.5 mmol) in anhydrous THF (50 mL) at 0°C. Stir the solution for 30 minutes at 0° C. Quench the reaction withsaturated ammonium chloride. Add EtOAc and wash with brine. Dry theorganic solution (Na₂SO₄), filter, and concentrate in vacuo. Purify byflash chromatography (silica gel, 0-30% EtOAc/hexanes and 30% ethylacetate/hexane) to yield[2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone10a (2.7 g, 93%) as a pale yellow oil. ¹H NMR (δ, 400 MHz, CDCl₃): 7.58(d, , 2H, J=8.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.76 (d, 1H, J=2.9 Hz),6.65 (d, 1H, J=8.8 Hz), 6.58 (dd, 1H, J=9.0, 2.9 Hz), 5.16 (d, 1H, J=6.8Hz), 5.14 (d, 1H, J=6.8 Hz), 5.04 (d, 1H, J=6.8 Hz), 5.00 (d, 1H, J=6.8Hz), 4.93 (d, 1H, J=6.8 Hz), 4.89 (d. 1H, J=6.8 Hz), 4.35-4.27 (m, 1H),3.92-3.82 (m, 1H), 3.44 (s, 3H), 3.43 (s, 3H), 3.42 (s, 3H), 2.22-2.10(m, 2H), 2.05-1.94 (m, 1H), 1.92-1.76 (m, 2H), 1.22 (d, 3H, J=6.2 Hz).HRMS calcd. 445.2226; found (electrospray, M+1) 445.2223.

Example 1 Preparation of(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro.cyclopenta[c]chromen-8-ol (11a)

To a solution of[2-(2,5-bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone10a (2.6 g, 5.8 mmol) in anhydrous methanol (232 mL) addp-toluenesulfonic acid (1.1 g, 5.8 mmol) and heat the resulting solutionto 50° C. for 18 hours under nitrogen. Cool the reaction to ambienttemperature and add bromocreosol green (10 mg) and sodiumcyanoborohydride (1.82 g, 29.0 mmol). Add methanol saturated with HCl(gas) drop wise until yellow color is maintained. Stir the reaction onehour past the time when no more color change is observed. Quench thereaction with saturated sodium bicarbonate, add EtOAc, and wash theorganic solution with sodium bicarbonate and brine. Dry the organicsolution over sodium sulfate, concentrate in vacuo, and purify by flashchromatography (silica gel, 0-40% EtOAc/hexanes and 40% ethylacetate/hexanes) to give4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4.9b-hexahydro-.cyclopenta[c]chromen-8-o11a (1.2 g, 4,0 mmol, 70%). ¹H NMR (δ, 400 MHz, MeOD) 7.23 (d, 2H, J=8.4Hz), 6.77 (d, 2H, J=8.4 Hz), 6.68 (d. 1H, J=8.8 Hz), 6.54 (d, 1H, J=2.6Hz), 6.50 (dd, 1H, J=8.6, 2.9 Hz), 3.45-3.38 (m, 1H), 2.63-2.55 (m, 1H),2.52-2.43 (m, 1H), 1.96-1.84 (m, 1H), 1.41-1.32 (m, 1H), 1.23-1.07 (m,2H), 0.87 (d, 3, J=6.6 Hz). MS calcd. 295.1; found (electrospray, M-I)295.1, HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then100% CH₃CN for 5 min; 1 mL/min; t_(r) 10.35 min). HPLC (Chiralpak AD,20-80% IPA/Heptane for 20 min; 1 mL/min; t_(R)=4.37 min).

Example 2 Preparation of(2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl-2-methyl-1,2,3,3a,4,9b.hexahydro-cyclopentan[c]chromen-8-ol

(2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(11a)

The enantiomer of example 1 was prepared in a manner substantiallysimilar to example 1 except the starting adipic acid 1a was racemic3-methyladipic acid. The two enantiomers were separated by chiralpreparative HPLC (Chiralpak AD, IPA/Heptane). ¹H NMR (δ, 400 MHz, MeOD)7.23 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.4 Hz), 6.68 (d, 1H, J=8.8 Hz),6.54 (d, 1H, J=2.6 Hz), 6.50 (dd, 1H, J=8.6, 2.9 Hz), 3.45-3.38 (m, 1H),2.63-2.55 (m, 1H), 2.52-2.43 (m, 1H), 1.96-1.84 (m, 1H), 1.41-1.32 (m,1H), 1.23-1.07 (m, 2H), 0.87 (d, 3H, 16.6 Hz). MS calcd. 295.1; found(electrospray, M-1) 295.1. HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂Ofor 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 10.35 min). HPLC(Chiralpak AD, 20-80% IPA/Heptane for 20 min; 1 mL/min; t_(R)9.4 min).

Example 3 Preparation of (2R,3aR,4S,9bS and (2,53aS,4R,9bR)-2-tert-Butyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-2-tert-Butyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9-hexahydro-cyclopenta[c]chromen-8-ol(11b)

Example 3 was prepared in a manner substantially similar to example 1except the starting adipic acid 1b was racemic 3-butyl adipic acid. Thetwo enantiomers were separated by chiral preparative HPLC (Chiralpak AD,IPA/Heptane).

Enantiomer A: ¹H NMR (δ, 400 MHz, MeOD): 7.24 (d, 2H, J=8.8 Hz), 6.78(d, 2H, J=8.4 Hz), 6.67 (d, 1H, J=8.8 Hz), 6.56 (d, 11H, J=2.7 Hz), 6.50(dd, 1H, J=8.6, 2.7 Hz), 4.88 (1H, obscured by MeOD), 3.46-3.37 (m, 1H),2.58-2.48 (m, 1H), 2.38-2.27 (m, 1H), 1.80-1.66 (m, 1H), 1.40-1.11 (m,3H), 0.71 (s, 9H). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1mL/min; t_(R)=3.13 min). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂Ofor 10 min then 100% CH₃CN for 5 min ; 1 mL/min; t_(r) 11.31. min).

Enantiomer B: ¹H NMR (δ, 400 MHz, MeOD): 7.24 (d, 2H, J=8.8 Hz), 6.78(d, 2H, J=84 Hz), 6.67 (d, 1H, J=8.8 Hz), 6.56 (d, 1H, J=2.7 Hz), 6.50(dd, 1H, J=8.6, 2.7 Hz), 4.88 (1H, obscured by MeOD), 3.46-3.37 (m, 1H),2.58-2.48 (m, 1H), 2.38-2.27 (m, 1H), 1.80-1.66 (m, 1H), 1.40-1.11 (m,3H), 0.71 (s, 9H). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1mL/min; t_(R)=5.60 min). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂Ofor 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 11.31 min).

Preparation 10 4-Oxo-tetrahydro-furan-3-carboxylic acid methyl ester(4a)

To a suspension of Nail (6.66 g, 166.5 mmol) in ether (500 mL) addmethyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction untilevolution of 12 gas ceases. Concentrate and dissolve the solid in DMSO(300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL,183.17 mmol) drop wise. Warm the reaction to room temperature and stirovernight. Acidify the reaction with 10% HCl and extract with ether(3×). Combine organic extracts and wash with brine. Dry the organicsolution (Na₂SO₄), filter, and concentrate in vacuo. Purify by flashchromatography (250 g SiO₂, 40 mL/min, 0-50% ethyl acetate/hexane for 20minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2mmol, 54%) as a colorless oil. ¹H NMR (δ, 400 MHz, CDCl₃): 4.50 (dd. 1H,J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, 1=16.8 Hz),3.79, (s, 3H), 3.97 (d, 11, J=16.8. Hz), 3.54 (t, 1H, J=8.4 Hz). MScalcd. 144; found (EI) 144.

Example 4 Preparation of (3aS,4S,9bS)- and(3aR,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol

(3aS,4S,9bS)- and(3aR,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol(11e)

Example 4 was prepared in a manner substantially similar to example 1except 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a was usedto make the enol triflate 3c. The two enantiomers were separated bychiral preparative HPLC (Chiralpak AD, MeOH).

Enantiomer A: ¹H NMR (δ, 400 MHz, MeOD): 7.27 (d, 2H, 1=8.8 Hz), 6.79(d, 2H, J=84 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.63-6.57 (m, 2H), 5.03 (d,1H, J=2.4 Hz), 4.14 (dd, 1H, J=8.6, 5.9 Hz), 3.81-3.75 (m, 2H),3.68-3,58 (m, 2H), 3.12 (dq, 1H, J=2.4, 8.8 Hz). HRMS (EI+) calcd284.1049; found: 284.1027. HPLC (Chiralpak AD, 20-80% IPA/Heptane for 20min; 1 mL/min; t_(R)=10.33 min). HPLC (Zorbax C18 column; 10 to 100%CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.29min).

Enantiomer B: ¹H NMR (δ, 400 MHz, MeOD): 7.27 (d, 2H, J=8.8 Hz), 6.79(d, 2H, J=8.4 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.63-6:57 (m, 2H), 5.03 (d,1H, J=2.4 Hz), 4.14 (dd, 1H, J=8.6, 5.9 Hz), 3.81-3.75 (m, 2H),3.68-3.58 (m, 2H), 3.12 (dq, 1H, J=2.4, 8.8 Hz). HRMS (EI+) calcd284.1049; found: 284.1088. HPLC (Chiralpak AD, 20-80% IPA/Heptane for 20min; 1 mL/min; t_(R)=13.31 min). HPLC (Zorbax C18 column; 10 to 100%CH₃CN/H₂ for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.29min).

Preparation 11 4-Oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester(4b)

To a solution of methyl thioglycolate (16.0 g, 0.15 mol) in MeOH (400mL) add NaOMe (8.04 g, 0.149 mol). Stir the reaction mixture at roomtemperature for 3 hours. Concentrate and dissolve the solid in DMSO (130mL). Cool the solution to 0° C. and add methyl acrylate (15.5 mL, 0.17mol) drop wise. Warm the reaction to room temperature and stir overnight(18 hours). Acidify with 10% HCl and extract with Et₂O (3×). Wash thecombine organic extracts with brine, dry (Na₂SO₄), filter andconcentrate in vacuo. Purify by flash chromatography (250 g SiO₂, 40mL/min, 0-30% EtOAc/Hexane for 15 minutes and then 30% EtOAc/Hexane for13 minutes) to afford a 1:1.5 mixture of two regioisomers (6.77 g, 48%)as a pale yellow oil with the major isomer being4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester 4b as a yellowoil. The material was used without further purification. MS calcd. 160;found (EI) 160.

Example 5 Preparation of (3aR,4S,9bS)- and(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cycloplenta[a]naphthalen-8-ol

(3aR,4S,9bS)- and(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol(11d)

Example 5 was prepared in a manner substantially similar to example 1except 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester 4b wasused to make the enol triflate 3d. The two enantiomers were separated bychiral preparative HPLC (Chiralpak AD, IPA/Heptane).

Enantiomer A: ¹H NMR (δ, 400 MHz, MeOD) 7.32 (d, 2H, J=8.3 Hz), 6.76 (d,2H, J=8.3 Hz), 6.72 (d, 1H, J=8.4 Hz), 6.66 (d, 1H, J=3.1 Hz), 6.59 (dd,1H, J=8.4, 3.1 Hz), 5.12 (s, 1H), 4.14 (dd, 1H, J=6.4, 1.5 Hz), 3.88(dd, 1H, J=5.4, 5.4 Hz), 2.64 (dd, 1H, J=10.1, 6.6 Hz), 2.55 (dd, 1H,J=12.3, 4.8 Hz), 2.47-2.38 (m, 1H), 2.29-2.18 (m, 1H). HPLC (Zorbax C18column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1mL/min; t_(r) 9.02 min). HPLC (Chiralpak AD, 30-70% IPA/Heptane for 10min; 1 mL/min; t_(R)=7.49 min). HRMS calcd for C₁₇H₁₇O₃S: 301.0898;found (ES+): 301.0897 (M+H).

Enantiomer B: ¹H NMR (δ, 400 MHz, MeOD) 7.32 (d, 2H, 1=8.3 Hz), 6.76 (d,2H, J=8.8 Hz), 6.72 (d, 1H, J=8.6 Hz), 6.66 (d, 1H, J=2.9 Hz), 6.59 (dd,1H, J=8.6, 2.9 Hz), 5.12 (s, 1H), 4.14 (dd, 1H, 1=6.2, 1,5 Hz), 3.87(dd, 1H, J=5.4, 5.4H-z), 2.64 (dd, 1H, J=10.1, 6.6 Hz), 2.55 (dd, 1H,=12.3, 4.8 Hz), 2.48-2.39 (m, 1H), 2.30-2.20 (m, 1H). HPLC (Zorbax C18column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min;1mL/min; t_(r) 9.02 min). HPLC (Chiralpak AD, 30-70% IPA/Heptane for 10min; 1 mL/min; t_(R)=8.9 min). HRMS calcd for C₁₇H₁₆O₃S: 300.0820; found(EI): 300.0789.

Example 6 Preparation of (2S,3a,4S,9bS)- or(2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cylopenta[a]naphthalen-8-ol

(2S,3aR,4S,9bS)- or(2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cyclopenta[a]naphtalen-8-ol(13)

To a solution of enantiomer A of4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[]naphthalen-8-ol 11d (20 mg, 0.066 mmol) in MeOH/H₂O (1:1, 3 mL) add.oxone (40 mg, 0.066 mmol). Stir the reaction at room temperature for 30minutes. Add 1.0 M Na₂SO₃ and stir the reaction for 5 minutes. Dilutewith EtOAc and wash with saturated sodium bicarbonate. Extract aqueouslayer with EtOAc (2×). Combine organic extracts, dry (Na₂SO₄), filterand concentrate to afford4-(4-hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2thia-cyclopenta[a]naphthalen-8-ol 13 (17 mg, 0.054 mmol, 85%). ¹H NMR(δ, 400 MHz, MeOD) 7.44 (d, 2H, J=8.8 Hz), 6.85 (d, 2R, J=8.8 Hz), 6.75(d, 1H, J=8.8 Hz), 6,70 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=8.8, 2.8 Hz).5.19 (s, 1H), 4.19 (dd, 1H, J=6.2, 6.2 Hz), 3.76 (d, 1H, J=7.9 Hz),3.06-2.94 (m, 1H), 2.84 (dd 1H, J=14.1, 5.3 Hz), 2.84 (dd, 1H, J=14.1,5.3 Hz), 2.62 (dd, 1H, J=13.0, 5.5 Hz), 2.29 (dt, 1H, J=5.2, 14.0 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min; 1 mL/min; t_(r) 7.17 min). LRMS calcd for C₁₇H₁₅O₄S: 315.1;found (ES−, M−H): 315.2.

Example 7 Preparation of (3aR,4S,9bS)- or(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁶-thia-cycopenta[a]naphthalen-8-ol

(3aR,4S,9bS)- or(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁶-thia-cyclopenta[a]naphthalen-8-ol(14)

To a solution of enantiomer A of4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol11d (10 mg, 0.033 mmol) in MeOH/H₂O (1:1, 3 mL) add oxone (40 mg, 0.066mmol). Stir the reaction at 50° C. for 2 hours. Add 1.0 M Na₂SO₃ andstir the reaction for 5 minutes. Dilute with EtOAc and wash withsaturated sodium bicarbonate. Extract aqueous layer with EtOCAc (2×).Combine organic extracts, dry (Na₂SO₄), filter and concentrate to afford4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁶-thia-cyclopenta[a]naphthalen-8-ol14 (8.5 mg, 0.025 mmol, 77%). ¹H NMR (δ, 400 MHz, MeOD) 7.47 (d, 2H,J-8.3 Hz), 6.87-6.74 (m, 4H), 6.67 (dd, 1H, J=8.6, 2.4 Hz), 5.25 (s,1H), 4.12-4.01 (m, 2H), 3.00 (m, 1H), 2.72 (dt, 1H, J=6.8, 12.8 Hz),2.63-2.53 (m, 1H), 2.52-2.42 (m, 1H). HPLC (Zorbax C18 column; 10 to100% CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r)7.68 min).

Preparation 12 6-methoxymethoxy coumarin (17a)

Equip a 3-L, three-neck, round-bottom flask equipped with a large blademechanical stirrer, a thermocouple, a Claisen adapter, an additionfunnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g,493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide(247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping thetemperature below 40° C. Rapidly stir the resulting mixture and heatgradually to 83° C. over 45 min, monitoring the temperature increase andgas evolution, Stir for 6 h at reflux then for 15 h at 76° C. Cool theresulting mixture to room temperature and quenched carefully with water(450 mL). Filter the solid, wash with heptane and dry under vacuum toafford 6-hydroxy coumarin (95 g) as a light brown solid which is usedwithout further purification. Equip a 2-L, three-neck, round-bottomflask with a magnetic stir bar and a thermocouple. Add 6-hydroxycoumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL)and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Addchloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over30 min while keeping the temperature below 40° C. Stir the resultingmixture at room temperature for 3 h, then add an additional equiv ofchloromethyl methyl ether. Stir at room temperature for 15 h, thenquench the reaction mixture with saturated aqueous ammonium chloride(500 mL) and extracted with ethyl acetate. Combine the organic extractsand dry over anhydrous magnesium sulfate, filter and concentrate underreduced pressure. Purify the residue by column chromatography on silicagel (30-50% ethyl acetate/heptane) to afford a light yellow solid.Suspend the solid in a mixture of ethyl acetatefleptane (150 mL, 10:90),filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) asa white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d J=7.8 Hz, 1H),7.30-7.12 (m, 3H), 6.41 (d, J=78 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6,118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (i),1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm⁻¹; ESI MS m/z 207[C₁₁H₁₀O₄+H]⁺.

Preparation 138-Methoxymethoxy-2-methylene-2,3,3a,9h-tetrahydro-1H-cyclopenta[c]chromen-4-one(18)

To a solution of 6-methoxymethoxy coumarin 17a (21 g, 0.102 mol) andPd(OAc)₂ (2.75 g, 0.012 mol) in 500 mL THF add2-(acetoxymethyl)allyl-trimethylsilane (26 mL, 0.122 mol) followed bytriisopropyl phosphite (18.1 mL, 0.073 mol). After stirring at 60° C.overnight, cool the solution to RT, concentrate under reduced pressure,and dilute with EtOAc. Wash the solution with saturated aqueous sodiumbicarbonate and brine. Dry over Na₂SO₄, and then concentrate to an oil.Purify the material by silica gel chromatography (Biotage 40M+65Mcolumns, 10 to 30% EtOAcHex over 60 min at 50 mL/min followed by 30 to50% EtOAc/Hex over 60 rain at 50 mL/min) to give 18.3 g (0.070 mol, 69%)of cyclopentanoid 18 and 3.8 g (18.3 mmol, 18%) of recovered startingmaterial. HRMS (ES+) calc for C₁₅H₁₇O₄: 261.1127, found: 261.1122 (M+1).

Preparation 148-Methoxymethoxy-2,3,3a,9b-tetrahydro-1H-spiro[cyclopenta[c]chromen-2,4′[1,3]dioxlan-4-one](19)

To a solution of cyclopentanoid 18 (17.7 g, 68 mmol) andN-methylmorpholine N-oxide (15.5 g, 132 mmol) in 375 mL t-butanol, 75 mLof THF, and 45 mL of water add osmium tetroxide (39 mL of a 2.5 wt %solution in t-butanol, 3.1 mmol). After stirring for 2 hrs, add asolution of 125 mL of saturated aqueous Na₂O₃ and 125 mL of saturatedaqueous sodium bicarbonate. After stirring for 1 hr, separate theaqueous solution and extract it 2× with EtOAc. Combine the organicsolutions and dilute with 300 mL EtOAc. Wash the organic solution with1:1 water:brine, brine, dry over Na₂SO₄, filter, and concentrate to awhite solid. To a suspension of the solid in 680 mL of CH₂Cl₂ and Et₃ N(38 mL, 273 mmol) cooled to 0° C. add phosgene (70 mL, 132 mmol). Afterstirring 4 hrs, quench the reaction with saturated aqueous sodiumbicarbonate. Wash the organic solution with 1 M HCl, saturated aqueoussodium bicarbonate, brine, dry over Na₂SO₄, filter and concentrate to awhite solid. Dissolve the solid in 50 mL of CH₂Cl₂ and then add 50 mLhexanes. After stirring for 30 min collect the precipitate by filtrationto give 10.3 g of cyclic carbonate 19. Concentrate the mother liquor andpurify by silica gel chromatography (Biotage 40L column, 0 to 100%EtOAc/1:1 CH₂Cl₂C:Hex over 60 min at 50 mL/min) to give another 3.23 gof cyclic carbonate 19 and 5.5 g of the minor diastereomer. HRMS (ES+)calc for CH₁₆H₁₇O₇: 321.0974, found: 321.0966 (M+H).

Preparation 15 Trifluoro-methanesulfonic acid8-methoxymethoxy-1,2,3,9b-tetrahydro-spiro[cyclopenta[c]chromen-2,4′-[1,3]dioxlan-4-yl]ester (20)

To a solution cyclic carbonate 19 (3.0 g, 9.37 mmol) in 70 mL of THF at−78° C. was added LiHMDS (13.1 mL of a 1 M solution in hexanes, 13.1mmol). After stirring for 30 min a solution ofN-phenyltrifluoromethanesulfonimide (4.68 g, 13.1 mmol) and HMPA (4.56mL, 26.2 mmol) in 10 mL THF was added via cannula. The solution waswarmed to 0° C. and after stirring for 30 min, saturated aqueousammonium chloride was added. The solution was diluted with EtOAc, washedwith water, brine, dried over Na₂SO₄, filtered, and concentrated.Purification by silica gel chromatography (Biotage 40M column, 0 to 30%EtOAc/1:1 CH₂Cl₂:Hexanes over 60 min at 50 mL/min) gave 2.5 g (5.53mmol, 59%) of enol triflate 20. ¹H NMR (δ, 400 MHz, CDCl₃): δ 6.96-6.90(m, 2H), 6.76 (m, 1H), 5.13 (s, 2H), 4.46 (d, 1H, J=8.8 Hz), 4,40 (d,1H, J=9.2 Hz), 4.23 (m, 1H), 3.47 (s, 3H), 3.12 (m, 1H), 2.96-2.87 (m,2H), 1.98 (t, 1H, J=12.3 Hz).

Preparation 168-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,9b-tetrahydro-spiro[cyclopenta[c]chromene-2,4′-[1,3]dioxlan](21)

To a solution of p-bromophenyl met oxymethyl ether (1.35 g, 6.22 mmol)in 28 mL of THF at −78° C. was added tBuLi (7.33 mL of a 1.7 M solutionin pentane, 12.46 mmol). After stirring for 10 ruin the solution waswarmed to 0° C. and a solution of ZnCl₂ (6.23 mL of a 1 M solution inether, 6.23 mmol) was added. The cold bath was removed and afterstirring for 10 min the solution was transferred to a solution of enoltriflate 20 (1.88 g, 4.16 mmol), Pd(PPh₃)₄ (720 mg, 0.623 mmol) in 7 nitof THF. The solution was warmed to 50° C. After stirring for 4 hrs, thesolutin was cooled to room temperature, diluted with EtOAc, washed withsaturated aqueous bicarbonate, brine, dried over Na₂SO₄, filtered, andconcentrated. The material was absorbed to 10 g of silica gel andpurified by silica gel chromatography (Biotage 40M column, 0 to 40%EtOAc/1Hexanes over 60 min at 50 mL/min) to give 1.06 g (2.41 mmol, 58%)of flavene 21. ¹H NMR (300 MHz, CDCl₃) δ 7.48 (m, 2H), 7.07 (m, 2H),7.03 (d, 1H, J=8.8 Hz), 6.92 (dd, 1H, J=8.8, 3.0 Hz), 6.79 (d, 1H, J=3.0Hz), 5.21 (s, 2H); 5:14 (s, 2H), 4.35 (d, 1H, J=8.8 Hz), 4.32 (d, 1H,J=8.8 Hz), 4.16 (m, 1H), 3.50 (s, 6H), 3.36 (dt, 1H, J=9.8, 6.0 Hz),3.36 (m, 1H), 2.93-2.85 (m, 2H), 1.92 (dd, 1H, J=13.2, 11.0 Hz).

Preparation 178-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-spiro[cyclopenta[c]chromene-2,4′-[1,3]dioxlan](22)

A solution of flavene 21 (1.06 g, 2.41 mmol) and 300 mg Pd/C in 8 mL ofTHF and 25 mL of MeOH was stirred under 60 psi H₂ for 2 hrs. Another 200mg of Pd/C and 4 mL of THF were added. After stirring for 2 hrs, thesolution was filtered through celite and the filter cake washed withMeOH/EtOAc. The combined organic filtrates were concentrated. Thematerial was adsorbed to 10 g silica gel and purified by silica gelchromatography (Biotage 40M column, 0 to 50% EtOA/Hexanes over 45 min at50 mL/min). Mixed fractions were re-purified (Biotage 40S column, sameconditions) to give 886 mg (2.0 mmol, 83%) of flavan 22. HRMS (ES+) calcfor C₂₄H₃₀NO₈: 460.1971, found: 460.1975 (M+NH₄).

Preparation 188-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one(23)

To a solution of flavan 22 (847 mg, 1.91 mmol) in 18 mL of THF was addeda solution of LiOH (230 mg, 9.58 mmol) in 9 mL of water. Add 8 mL of THFand 4 mL of water. After stirring for 1 hr, NaH₂ PO₄ (9.6 mL of a 1 Msolution in water, 9.6 mmol) was added followed by NalO₄ (2.0 g, 9.35mmol). After stirring for 1 hr, the solution was diluted with EtOAc. Theaqueous solution was separated and extracted with EtOAc, The combinedorganic solutions were washed with 1:1 saturated aqueousNa₂SO₃:bicarbonate, brine, dried over Na₂SO₄, filtered, and concentratedto give 760 mg, 1.97 mmol, 100% of cyclopentanone 23. ¹H NMR (400 MHz,CDCl₃) δ 7.35 (d, 2H, J=8.8 Hz), 7.06 (d, 2H, J=8.7 Hz), 6.90-6.81 (m,3H), 5.19 (s, 2H), 5.14-5.08 (m, 3H), 3.87 (t, 1H, J=7.5 Hz), 3.49 (s,3H), 3.48 (s, 3H), 2.93 (m, 1H), 2.78 (dd, 1H, J=18.5, 8.41z), 2.63 (d,1H, J=18.5 Hz), 2.33 (dd, 1H, J=18.6, 12.1 Hz), 2.04 (dd, 1H, J=18.6,8.1 Hz).

Example 8 Preparation of (3aR,4S,9bS)- and(3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,3a-4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one

(3aR,4S,9bS)- and(3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one(24)

Stir a solution of cyclopentanone 23 (384 mg, 1.0 mmol) in 10 mL of THFand 8 mL of 3 M HCl overnight. Dilute the solution with EtOAc. Separatethe aqueous solution and extract 2× with EtOAc. The combined organicsolutions were washed with saturated aqueous sodium bicarbonate, brine,dried over Na₂SO₄, filtered, and concentrated to afford 304 mg ofcyclopentanone 24. The material was purified by preparative chiralchromatography (Chiralpak AD, 65/35 heptane/ethanol).

Enantiomer A: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL; 1 min; t_(r) 8.34 min). HPLC (ChiralpakAD, 65/35 heptane/ethanol, 1 mL/min; t_(R)=4.1 min). LRMS (ES−) calcdfor C₁₈H₁₅O₄: 295.10; found: 295.29 (M−H).

Enantiomer B: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.37 min). HPLC (ChiralpakAD, 65/35 heptane/ethanol, 1 mL/min; t_(R)=5.3 min). LRMS (ES−) calcdfor C₁₈H₁₅O₄: 295.10; found: 295.29 (M−H).

Preparation 198-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ol(25)

To a solution of cyclopentanon 23 (60 mg, 0.16 mmol) in 1 mL of MeOH and0.5 mL of THF was added NaBH₄ (15 mg, 0.40 mmol). After stirring for 2hrs saturated aqueous ammonium chloride was added. The solution wasdiluted with EtOAc. The aqueous solution was extracted 2× with EtOAc.The combined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated to give 60 mg (0.16 mmol, 100%) of alcohol 25.HRMS(ES+) calc for C₂₂H₃₀NO₆: 404.2073, found: 404.2082 (M+NH₄).

Example 9 Preparation of (2R,4s,9bS:)- and(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2,8-diol

(2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2,8-diol(26)

Stir a solution of alcohol 25 (60 mg, 0.16 mmol) in 2 mL of THF and 2 mLof 3 M HCl overnight. Dilute the solution with EtOAc. Separate theaqueous solution and extract 2× with 10% MeOH in EtOAc. Wash thecombined organic solutions with saturated aqueous sodium bicarbonate,brine, dry over Na₂SO₄, filter, and concentrate. Absorb to 1 g silicagel. Purify by silica gel chromatography (4 g silica gel, 0 to 10%MeOH/CH₂Cl₂ then 20% MeOH/CH₂Cl₂) to give 37 mg, (0.12 mmol, 79%) ofalcohol 26. HPLC (Zorbax C18 column 10 to 100% CH₃CN/H₂O for 10 min then100% CH₃CN for 5 min; 1 mL/min; t_(r) 7.79 in). LRMS (ES−) calcd forC₁₈H₁₅O₄: 297.11; found: 297.29 (M−H).

Preparation 208-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ol(27)

Cool a solution of alcohol 25 (50 mg, 0.13 mmol), triphenylphosphine (68mg, 0.26 mmol), benzoic acid (24 mg, 0.2 mmol) to 0° C. Add diisopropylazodicarboxylate (50 ul, 0.26 mmol) slowly so that temperature ofreaction does not rise above about 4° C. After addition is complete,remove ice bath and warm the reaction to room temperature and stirovernight. Add MeOH to the reaction mixture and stir for 15 minutesbefore concentrating to a yellow oil. Purify by flash chromatography (10g SiO₂, 40 n/min, 0-40% EtOAc/Hexanes over 20 minutes and 40%EtOAc/Hexane for 13 minutes) to yield 67 mg of a clear oil. To asolution of the clear oil (64 mg, 0.13 mmol) in THF:H₂O (1:1, 4 mL) addlithium hydroxide (4 mg, 0.13 mmol) and stir the reaction at roomtemperature overnight. Heat the mixture to 60° C. with stirring for 2hours. Cool the mixture to room temperature and neutralize with 1.0 NHCl. Dilute with EtOAc and wash with saturated sodium bicarbonate andbrine. Dry the organic solution (Na₂SO₄), filter and concentrate invacuo. Purify by flash chromatography (10 g SiO₂, 40 mL/min, 0-70%EtOAc/hexanes over 20 minutes and then 70% EtOAc/hexanes for 13 minutes)to give 41 mg (0.106 mmol, 82%) of alcohol 27 as a colorless oil. ¹H NMR(δ, 400 MHz, CDCl₃) 7.36 (d, 2H, J=8.8 Hz), 7.05 (d, 21H. J=8.8 Hz),6.86-6.79 (m, 31), 5.19 (s, 2H), 5.13 (d, 1H, J=6.8 Hz), 5.10 (d, 1H,6.8 Hz), 5.07 (d, 1H, J=2.2 Hz), 4.32 (m, 1H), 3:65 (dt, 1H, J=3.5, 8.4Hz), 3.50 (s, 31-1), 3.49 (s, 31), 2.99 (m, 1H), 2.27 (m, 1H), 2.07(ddd, 1H, J=3.9, 5.6, 13.6), 1.87 (dd, 1H, J=5.2, 11.6, 13.6 Hz), 1.42(m, 1H), 1.27 (s, 1H). HRMS (ES+) calcd for C₂₂H₃₀NO₆: 404.2073; found:404.2057 (M+NH₄).

Preparation 212,2-Difluoro-8-methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene(29)

Stir a solution of cyclopentanone 23 (273 mg, 0.710 mmol) in 0.5 mL of(diethylamino)sulfur trifluoride and 0.5 mL of dichloroethane in a 4 mLvial at 40° C. overnight. Dilute with CH₂Cl₂ and wash 2× with saturatedaqueous sodium bicarbonate. Dry the organic solution over Na₂SO₄,filter, and concentrate. Absorb to 5 g of silica gel and purify bysilica gel chromatography (35 g silica gel, 0 to 30% EtOAc/Hexanes over48 min at 35 mL/min) to give 217 mg (0.53 mmol, 75%) ofdifluorocyclopentane 29. ¹H NMR (δ, 400 MHz, CDCl₃) 7.34 (d, 2H, J=8.4Hz), 7.06 (d, 2H, J=8.4 Hz), 6.90-6.83 (m, 2H), 6.80 (s, 1H), 5.19 (s,2H), 5.13 (d, 1H, J=6.8 Hz), 5.11 (d, 1H, J=6.8 Hz), 5.02 (s, 1H), 3.67(t, 1H, J=8.2 Hz), 3.49 (s, 6H), 2.89-2.67 (m, 2H), 2.40-2.09 (m, 2H),1.88 (dt, 1H, J=14.3, 7.0 Hz).

Example 10 Preparation of (3aR,4S,9bS)- or(3aS,4R,9R)-2,2-Difluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(3aR,4S,9bS)- or(3aS,4R,9bR)-2,2-Difluoro-4-(4-hydroxy-phenyl)1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(30)

Stir a solution of difluorocyclopentane 29 (196 mg, 0.480 mmol) in 7 mLof THF and 3 mL of 3 M HCl overnight. Add 1 mL of 5 M HCl and let stirovernight. Dilute the solution with EtOAc. Separate the aqueous solutionand extract 2× with EtOAc. The combined organic solutions were washedwith saturated aqueous sodium bicarbonate, brine, dried over Na₂SO₄,filtered, and concentrated. Absorb to 2 g of silica gel and purify bysilica gel chromatography (10 g silica gel, 10 to 60% EtOAc/Hexanes over30 min at 35 mL/min) to give 155 mg (0.48 mmol, 100%) ofdifluorocyclopentane 30. The enantiomers were separated by preparativechiral chromatography (Chiralpak AD, 65/35 heptane/ethanol).

Enantiomer A: HPLC (Zorbax C18 colun; 10 to 100% CH₃CN/H₂O for 10 rainthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.61 min). HPLC (ChiralpakAD, 20/80 IPA/Heptane, 1 mL/min; t_(R)=8.8 min). HRMS (CI+) calcd forC₁₈H₁₇F₂O₃: 319.1146; found: 319.1151 (M+H).

Enantiomer B: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.60 min). HPLC (ChiralpakAD, 20/80 IPA/Heptane, 1 mL/min; t_(R)=16.0 min). HRMS (CI+) calcd forC₁₈H₁₇ F₂O₃: 319.1146; found: 319.1164 (M+H).

Preparation 228-Methoxymethoxy-4-(4-methoxymethoxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene(32 and 33)

Add tetrabutylammonium fluoride (0.075 mL of a 1.0 M solution in THF0.075 mmol) to a solution of cyclopentanone 23 (288 rag, 0.75 mmol) and(trifluoromethyl)trimethylsilane (3.75 mL of a 0.5 M solution in THF,1.875 mmol) in 5 mL of THF. After stirring for 2 his, add another 1.5 mLof (trifluoromethyl)trimethylsilane and 0.030 mL of tetrabutylammoniumfluoride, After stirring for 1 hr, add another 0.75 mL of(trifluoromethyl)trimethylsilane and 0.015 mL of tetrabutylammoniumfluoride. After stirring for 30 min, add saturated aqueous ammoniumchloride, Extract the aqueous solution with EtOAc. Combine the organicsolutions and wash with water, brine, dry over Na₂SO₄, filter andconcentrate to an oil. To a solution of the oil in 5 mL of THF add TBAF(0.75 mL of a 1.0 M solution in THF, 0.075 mmol). After stirring for 15min add saturated aqueous sodium bicarbonate. Extract the aqueoussolution with EtOAc. Combine the organic solutions and wash with water,brine, dry over Na₂SO₄, filter and concentrate to 350 mg of an oil whichwas used without further purification. To a solution of the oil, DMAP(10 mg, 0.08 mmol) and Et₃N (0.325 mL, 2.26 mmol) in 4 mL ofdichloromethane add methyl chloroglyoxylate (0.105 mL, 1.14 mmol). Afterstirring for 1 hr, add. another 0.16 mL of Et₃ N and 0.050 mL of methylchloroglyoxylate. After stirring for 30 min dilute the solution with.EtOAc, wash with saturate aqueous sodium bicarbonate, brine, dry overNa₂SO₄, filter and concentrate. Absorb to 2 g of silica gel and purifyby silica gel chromatography (10 g silica gel, 0 to 30% EtOAc/Hexanesover 20 min and then 30% EtOAc/Hexanes at 35 mL/min) to give 360 mg(0.67 mmol, 89%) of an oil which was used without further purification.A solution of the oil (320 mg, 0,59 mmol), triphenylsilane (625 rug,1.78 mmol), and AIBN (15 mg, 0.091 mmol) in 6 nm of toluene was heatedto 80° C. for 4 hrs. The solution was cooled to room temperature,filtered, and the precipitate washed with Et₂O. Combine the filtratesand concentrate. Absorb to 2 g of silica gel and purify by silica gelchromatography (35 g silica gel, 0 to 30% EtOAc/Hexanes over 48 min at35 mL/min) to give 114 mg (0.26 mmol, 44%) of trifluoromethyl 32 and 136mg (0.31 mmol, 52%) of trifluoromethyl 33. The structures were assignedby 2D NMR spectroscopy (gDQCOSY, edited HSQC, and 2D-NOESY).Trifluoromethyl 32: HRMS (FAB) calcd for C₂₃H₂₅F₃O₅: 438.1654; found:438.1657 (M+H). Trifluoromethyl 33: HRMS (FAB) calcd for C₂₃H₂₅F₃O₅:438.1654; found: 438.1657 (M+H).

Example 11 Preparation of (2S,3aR,4S 9bS)- and(2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2S,3aR,4S,9bS)- and(2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(34)

Stir a solution of trifluoromethyl 32 (105 mg, 0.240 mmol) in 4 mL ofTHF and 2 mL of 3 M HCl overnight. Add 1 mL of THF and 0.5 mL of 12 MHCl. After stirring for 6 hrs, dilute the solution with EtOAc. Separatethe aqueous solution and extract 2× with EtOAc, Wash the combinedorganic solutions with saturated aqueous sodium bicarbonate, brine, dryover Na₂SO₄, filter, and concentrate. Absorb to 2 g of silica gel andpurify by silica gel chromatography (10 g silica gel, 0 to 40%EtOAc/Hexanes over min at 35 mL/min) to give 62 mg (0.18 mmol, 74%) oftrifluoromethyl 34. The enantiomers were separated by preparative chiralchromatography (Chiralpak AD, IPA/heptane).

Enantiomer A: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r)=10.32 min). 1HPLC (ChiralpakAD, 30/70 IPA/Heptane, 1 mL/min; t_(R)=2.53 min). HRMS (ES−) calcd forC₁₉H₁₆F₃O₃: 349.1052; found: 349.1059 (M−H).

Enantiomer B: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 10.32 min). HPLC (ChiralpakAD, 30/70 IPA/Heptane, 1 mL/min; t_(R)=3.68 min). HRMS(ES−) calcd forC₁₉H₁₆F₃O₃: 349.1052; found: 349.1078 (M−H).

Example 12 Preparation of (2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl-2-trifluoromethyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl.1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol (35)

Stir a solution of trifluoromethyl 33 (125 mg, 0.290 mmol) in 4 mL ofTHF and 2 mL of 3 M HCl overnight. Add 1 mL of THF and 0.5 mL of 12 MHCl. After stirring for 6 hrs, dilute the solution with EtOAc. Separatethe aqueous solution and extract 2× with EtOAc. Wash the combinedorganic solutions with saturated aqueous sodium bicarbonate, brine, dryover Na₂SO₄, filter, and concentrate. Absorb to 2 g of silica gel andpurify by silica gel chromatography (10 g silica gel, 0 to 50%EtOAc/Hexanes over min at 35 mL/min) to give 92 mg (0.18 mmol, 91%) oftrifluoromethyl 35. The enantiomers were separated by preparative chiralchromatography (Chiralpak AD, IPA/heptane).

Enantiomer A: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 10.13 min). HPLC (ChiralpakAD, 30/70 IPA/Heptane, 1 mL/min; t_(R)=2.96 min). HRMS(ES−) calcd forC₁₉H₁₆F₃O₃: 349.1052; found: 349.1086 (M−H).

Enantiomer B: HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 10.13 min). HPLC (ChiralpakAD, 30/70 IPA/Heptane, 1 mL/min; t_(R)=4.66 min). HRMS(ES−) calcd forC₁₉H₁₆F₃O₃: 349.1052; found: 349.1064 (M−H).

Preparation 232-Ethyl-8-methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ol(31)

Heat CeCl₃-7H₂O (97 mg, 0.26 mmol) under vacuum at 70° C. for two hoursand then warm slowly to 120° C. and continue heating overnight. Cool toroom temperature and add THF (3 mL) followed by cyclopentanone 23 (100mg, 0.26 mmol) and stir the solution for 45 minutes. Cool the reactionto −10° C., add EtMgCl (3.0 M in THF, 87 ul, 0.26 mmol) and stir thereaction for 30 minutes. Quench the reaction with saturated aqueous NH₄Cl and extract with EtOAc (2×), Combine the organic extracts, wash withbrine, dry (Na₂SO₄), filter and concentrate. Purify by flashchromatography (10 g silica gel, 40 mL/min, dry loading on 700 mg ofsilica gel, 0-30% EtOAc/hexanes for 20 minutes and 30% EtOAe/hexanes for13 minutes) to afford Alcohol 31 (86 mg, 0.207 mmol, 81%). ¹H NMR (δ,400 MHz, CDCl₃) 7.36 (d, 21, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz),6.90-6.87 (m, 2H), 6.83 (dd, 1H, J==8.8, 2.6 Hz), 5.19 (s, 2H) 5.14 (d,, J=68 Hz), 5.10 (d, 1H, J=6.8 Hz), 5.05 (d, 1H, J=2.2 Hz), 3.54 (dd,1H, J=7.6, 7.6 Hz), 3.51 (s, 3H), 3.49 (s, 3H), 2.70 (ddd, 1H, J=2.2,7,6, 9.6 Hz), 2.22 (dd, 1H, J=13.6, 7.9 Hz), 2.03 (d, 1H, J=13.6 Hz),1.84 (dd, 1H, J=14.1, 10.1 Hz), 1.67 (dd, 1H, J=14.1, 9.2 Hz), 1.52 (m,2H), 0.89 (t, 3H, J=7.3 Hz).

Example 13 Preparation of (2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9bR-hexahydro-cyclopenta[c]chromene-2,8-diol

(2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cylopenta[c]chromene-2,8-diol(37)

Dissolve alcohol 36 (80 mg, 0.19 mmol) in THF (2 mL) and add 3 M I—HC(2.0 mL). Stir the reaction at room temperature overnight. Dilute thereaction with EtOAc and wash with saturated aqueous sodium bicarbonateand brine. Extract the aqueous solutions with EtOAc (1×). Combineorganic solutions, dry (Na₂SO₄), filter and concentrate in vacuo. Purifyby flash chromatography (10 g SiO₂, dry loading on 700 mg silica gel, 40ml/min, 040% EtOAc/Hexane over 25 minutes and then 40% EtOAc/hexane for7 minutes) to afford alcohol 37 (20 mg, 0.061 mmol, 32%) as a whitesolid. HRMS (ES+) calcd for C₂₀H₂₃O₄: 327.1596; found: 327.1596 (M+H).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min; 1 mL/min; t_(r) 8.6 min).

Preparation 242-Ethyl-8-methoxymethoy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene(38)

Prepare a solution of alcohol 31 (145 mg, 0.32 mmol). DMAP (5 mg, 0.035mmol), and Et₃ N (146 ul, 1.05 mmol) in CH₂Cl₂ (4 mL). Add methylchloroglyoxylate (46 ul, 0.52 mmol) drop wise. Stir the reaction underN₂ for 30 minutes. Dilute with EtOAc and wash with saturated aqueoussodium bicarbonate, 1.0 M HCl, saturated aqueous sodium bicarbonate andbrine. Dry the organic solution over Na₂SO₄, filter, and concentrate invacuo. Purification by flash chromatography (10 g SiO₂, 40 mL/min, dryloading on 500 mg silica, 0-30% EtOAc/Hexanes for 20 minutes and then30% EtOAc/Hexanes for 13 minutes) afforded 142 mg (0.28 mmol, 81%) of anoil which was used without further purification. Dissolve the oil (138mg, 0.28 mmol) and triphenhyl tinhydride (290 mg, 0.83 mmol) in toluene(5 mL). Add AIBN (7 mg, 0.04 mmol) and heat the solution to 80° C. andstir for 18 hours Filter the precipitate and wash with ether. Combinethe filtrates, concentrate and purify by flash chromatography (10 gSiO₂, 40 mL/min, dry loading on 800 mg silica, 0-30% EtOAc/Hexane over20 minutes and then 30% EtOAc/hex for 13 minutes) to afford 107 mg (0.27mmol, 99%) of alkyl cyclopentane 38 as a 4:1 mixture of diastereomers.HRMS(ES+) calcd for C₂₄H₃₄NO₅: 416.2437; found: 416.2432 (M+NH₄).

Example 14 Preparation of (2S,3aS,4R,9bR)- and (2R,3aS,4R,9bR)- and(2S,3aR,4S,9bS)- and(2R,3aR,4S,9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2S,3aS,4R,9bR)- and (2R,3aS,4R,9bR)- and (2S,3aR,4S,9bS)- and(2R,3aR,4S,9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(39)

Dissolve alkyl cyclopentane 38 (109 mg, 0.27 mmol) in THF (4 mL) thenadd 3 M HCl (1.0 mL). Stir the reaction at room temperature overnight.Dilute the reaction with EtOAc and wash with saturated aqueous sodiumbicarbonate and brine, Extract the aqueous layer with EtOAc (1×).Combine the organic extracts, dry (Na₂SO₄), filter and concentrate invacuo. Purify by flash chromatography (10 g SiO₂, dry loading on 700 mgsilica, 40 mL/min, 0-30% EtOAc/Hexane over 25 minutes and then 30%EtOAc/hexane for 7 minutes) to afford 56 mg (0.18 mmol, 68%) of alkylcyclopentane 39 as a white solid. HRMS(ES+) calcd for C₂₀H₂₆NO₃:328.1913; found: 328.1906 (M+NH₄). HPLC (Zorbax C18 column; 10 to 100%CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.33min).

Preparation 252-Methoxy-8-methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene(40)

To a solution of alcohol 25 (200 mg, 0.52 mmol) in DMF (5 mL) add sodiumhydride (60% dispersion in mineral oil, 21 mg, 0.51 mmol) and stir thereaction at room temperature for 10 minutes. Cool the reaction to 0° C.and add methyl iodide (33 ul, 0.52 mmol) and stir the reaction mixturefor 2 hours. Quench the reaction with saturated NH₄ Cl and extract withEtOAc (2×). Combine the organic extracts and wash with H₂O, saturatedaqueous sodium bicarbonate and brine. Dry (Na₂SO₄), filter andconcentrate the solution in vacuo. Purify by flash chromatography (10 gSiO₂, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40%EtOAc/Hexanes for 13 minutes) to methyl ether 40 (210 mg, 0.52 mmol,100%) as a yellow oil HRMS(ES+) calcd for C₂₃H₂₉O₆: 401.1964; found;401.1969 (M+H).

Example 15 Preparation of (2S,3aS,4R,9bR)- and(2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-methoxy-1,2,3,3a-4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2S,3aS,4R,9bR)- and(2R,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-methoxy-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(41)

Dissolve methyl ether 40 (205 nag, 0.51 mmol) in THF (8 mL) and add 3 MHCl (2 mL). Stir the reaction at room temperature overnight. Dilute thereaction with EtOAc and wash with saturated aqueous sodium bicarbonateand brine. Extra the aqueous solutions with EtOAc (1×). Combine theorganic solutions, dry (Na₂SO₄), filter and concentrate them in vacuo.Purify the product by flash chromatography (10 g SiO₂, dry loading on700 mg silica, 40 ml/min, 0-50% EtOAc/Hexane over 20 minutes and then50% EtOAc/hexane for 13 minutes) to afford methyl ether 41 (125 mg, 0.4mmol, 78%) as a white solid. HRMS(ES+) calcd for C₁₉H₂₃NO₄: 330.1705;found: 330.1695 (M+NH₄); HPLC (Zorbax C18 columnn; 10 to 100) %CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.95min). The enantiomers wre separated by preparative chiralchromatography, chiralpol AD, IPA/Heptane.

Enantiomer A: HRMS (ES+) calcd for C₉H₂₄NO₄: 330.1705; found: 330.1691(M+NH₄). HPLC (Chiralpak AD, 30-70% IPA/Heptane for 15 min; 1 mL/min;t_(R)=3.52 min). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.95 min).

Enantiomer B: HRMS(ES+) calcd for C₁₉H₂₄NO₄: 330.1705; found: 330.1695(M+NH₄). HPLC (Chiralpak AD, 30-80% IPA/Heptane for 15 min; 1 mL/min;t_(R)=6.15 min). HPLC (Zorbax 18 column; 10 to 100% CH₃CN/H₂O for 10ruin then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 8.96 min).

Preparation 25 Acetic acid8-methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ylester (42)

Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200mg, 0.52 mmol), Et₃ N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol)in CH₂Cl₂ (5 mL) and stir the reaction at room temperature for 1 hour.Dilute the solution with EtOAc and wash with H₂O, saturated aqueoussodium bicarbonate and brine. Dry (Na₂SO₄), filter and concentrate thesolution in vacuo. Purify the product by flash chromatography (10 gSiO₂, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40%EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol,83%) as a yellow oil. HRMS(FAB+) calecd for C₂₄H₂₈O₇: 428.1835; found:428.1833 (M+).

Example 16 Preparation of (2S,3aS,4R,9bR)- and (2R,3aR,4S,9bS)-Aceticacid8-hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9-hexahydro-cyclopenta[c]chromen-2-ylester

(2S,3aS,4R,9bR)- and (2R,3aR,4S,9bS)-Acetic acid8-hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ylester (43)

Dissolve acetate 42 (180 mg, 0.42 mmol) in THF (8 mL) and add 3 M HCl (2mL). Stir the reaction at room temperature overnight. Dilute thereaction with EtOAc and wash with saturated aqueous sodium bicarbonateand brine, Extract the aqueous solutions with EtOAc (1×). Combine, dry(Na₂SO₄), filter and concentrate the organic solutions in vacuo. Purifythe product by flash chromatography (10 g SiO₂, dry loading on 700 mgsilica, 40 ml/min, 0-50% EtOAc/Hexane over 20 minutes and then 50%EtOAc/hexane for 13 minutes) to afford acetate 43 (47 mg, 0.14 mmol,33%) as a white solid. The enantiomers were separated.

Enantiomer A: HRMS(ES+) calcd for C₂₀H₂₄NO₅: 358.1654; found: 358.1636(M+NH₄). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1 mL/min;t_(R)=3.73 min). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.07 min).

Enantiomer B: HRMS(ES+) calcd for C₂₀H₂₄NO₅: 358.1654; found: 358.1641(M+NH₄). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1 mL/min;t_(R)=5.35 min). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/1120 for 10min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.07 min).

Preparation 262-Fluoro-8-methoxymethoxy-4-(4-methoxymethoxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene(44)

Dissolve alcohol 25 (120 rag, 0.32 mmol) in CH₂Cl₂ (5 mL). AddN,N-diethyl amino sulfurtrifluride (0.8 mL, 6.0 mmol) and stir thereaction at room temperature overnight. Dilute the reaction with CH₂ Cl₂and wash with saturated aqueous sodium bicarbonate. Extract the aqueouslayer with CH₂Cl₂ (1×). Combine the organic extracts, dry (Na₂SO₄),filter and concentrate them in vacuo. Purify the product by flashchromatography (10 g SiO₂, 40 mL/min, dry loading on 800 mg silica,10-30% EtOAc/hexane over 33 minutes) to afford fluororcyclopentane 44(84 mg, 0.217 mmol, 70%). HRMS(ES+) calod for C₂₂H₂₆FO₅: 389.1764;found: 489.1761 (M+H).

Example 17 Preparation of (2R,3aS,4R,9bR)- and(2S,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a-4,9b-hexahydro-cyclopenta[c]chromen-8-ol

(2R,3aS,4R,9bR)- and(2S,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexyhydro-cyclopenta[c]chromen-8-ol(45)

Dissolve fluorocyclopentane 44 (78 mg, 0.201 mmol) in THF (2 mL) and add3 M HCl (0.5 mL). Stir the reaction at room temperature overnight.Dilute the reaction with EtOAc and wash with saturated aqueous sodiumbicarbonate and brine. Extract the aqueous solutions with EtOAc (1×).Combine the organic extracts, dry (Na₂SO₄), filter and concentrate themin vacuo. Purify the product by flash chromatography (10 g SiO₂, dryloading on 700 mg silica, 40 ml/min, 0-30% EtOAc/Hexane over 20 minutesand then 30% EtOAc/hexane for 13 minutes) to afford fluorocyclopentane45 (54 rag, 0.18 mmol, 90%) as a white solid. The enantiomers wereseparated by preparative chiral chromatography (Chiralpak AD,IPA/heptane).

Enantiomer A: HRMS(ES+) calcd for C₁₈H₁₇FO₃: 301.1240; found: 301.1221(M+H). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1 mL/min;t_(R)=5.88 ml). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.46 min).

Enamtiomer B: HRMS(ES+) calcd for C₁₈H₁₈FO₃: 301.1240; found:301,1226(M+H). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 15 min; 1 mL/min;t_(r)=7.13 min), HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10min then 100% CH₃CN for 5 min; 1 mL min; t_(r) 9.49 min).

Example 18 Preparation of (2S,3aS,4R,9bR)- and(2R,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,49b-hexahydro-cyclopenta[c]chromen-8-ol

(2S,3aS,4R,9bR)- and(2R,3aR,4S,9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol(47)

Fluorocyclopentane 47 was prepared from alcohol 27 in a mannersubstantially similar to fluorocyclopentane 45. HRMS (ES+) calcd forC₁₈H₁₈FO₃: 301.1240; found: 301.1241 (M+H).

Preparation 27 6-Benzyloxy-2-oxo-2H-chromene-3-carboxylic acid ethylester

To a 0 C solution of the phenol (26.7 g, 114 mmol) and benzyl bromide(20.5 mL, 171 mmol) in DMF (300 mL) add Nail (6.84 g, 1.5 mmol)portionwise over 15 min. Allow venting during the addition, during whichtime the solution turns dark red. After min, remove the cooling bath andallow the solution to warm to 23 C, during which time a precipitateforms and the solution turns dark brown. After 2 h, slowly pour thesolution into ½ satd. NaHCO₃ (500 mL), and filter the mixture. Wash thefilter cake with H₂O (2×300 mL) and 50% Et₂O/hexanes (2×300 ml.) toremove remaining aqueous salts and excess benzyl bromide. Dry theremaining yellow solid to afford Preparation 27 (28.9 g, 78%). ¹H NMR(d-DMSO) δ 8.67 (s, 1H), 7.57 (s, 1H), 7.37-7.47 (m, 7H), 5.15 (s, 2H),4.28 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).

Preparation 282-Benzyloxy-6,9-dioxo-8,9,10,10a-tetrahydro-7H-benzo[e]chromene-6a-carboxylicacid ethyl ester

Heat a suspension of Preparation 27, (12.0 g, 37.0 mmol),2-trimethylsilyloxybutadiene (7.1 g, 55.5 mmol) and hydroquinone(0.040g) in o-xylenes (40 mL) to 135 C for 24 h. Allow the reaction tocool to 23 C, then pour the contents into a solution of HOAc (5 mL) inTBAF (70 mL, 1 M in THF, 70 mmol). Stir the resulting solution for 1hour at 23 C, then slowly pour the contents into ½ satd. NaHCO₃ (150 mL)and EtOAc (250 mL.), Separate the layers and wash the organic extractwith brine (150 mL), dry over Na₂SO₄, and concentrate to afford a brownsemisolid, Purify the product by MPLC (0 to 15 to 30% EtOAc/hexanes) toafford Preparation 28 (9.3 g, 63%) as a white solid ¹H NMR (CDCl₃) δ7.31-7.42 (m, 5H), 7.04 (d, J=8.8 Hz, 1H), 6.90 (dd, J=2.8, 8.8 Hz, 1H),6.73 (d, J=2.8 Hz, 1H), 5.03 (d, 2H), 3.98-4.16 (m, 2H). 3.66 (dd,J=3.2, 13.2 Hz, 1 t), 2.88 (m, 1H), 2.58-2.72 (m, 2H), 2.49 (m, 1H),2.38 (t, J=13.6 Hz, 1H), 2.24 (td, J=13.6, 5.2 Hz, 1H), 1.01 (t, J=7.2Hz, 3H).

Preparation 292-Benzyloxy-7,8,10,10a-tetrahydro-6aH-benzo[c]chromene-6,9-dione

To a solution of Preparation 28 (9.25 g, 23.5 mmol) in THF (75 mL), EtOH(25 mL), and H₂O (40 mL) add lithium hydroxide hydrate (4.92 g, 117mmol). Attach the flask to a reflux condenser and heat to 60 C for 1 h.Allow the contents to cool to 23 C and pour them into 1 N HCl andextract with Et₂O (2×75 mL.) and EtOAc (2×75 mL). Wash the combinedorganic extracts with brine, dry over Na₂SO₄, and concentrate to affordthe intermediate carboxylic acid as an off-white solid, which is usedimmediately in the next step.

Add o-xylenes (100 mL) to the flask containing the crude acid, and heatthe resulting heterogeneous solution to reflux for 2 h. Concentrate themixture via rotary evaporator to afford Preparation 29 (approx. 9 g,˜quantitative) as an approximately 3:1 inseparable mixture ofdiastereomers. No further purification is required. ¹H NMR (CDCl₃) δ7.30-7.44 (m, 5H), 7.02 (d, J -8.8 Hz, 1H), 6.89 (dd, J=8.8, 2.8 Hz,1H), 6.74 (d, J=2.8 Hz, 1H), 5.04 (s, 3H), 3.02-3.36 (m, 2H), 2.54-2.77(m, 3H), 2.36-2.45 (m, 2H), 1.93-2.02 (1,1H).

Preparation 30

To a solution of Preparation 29 (˜9g, ˜23 mmol) and ethylene glycol (279mL, 50 mmol) in toluene (135 mL) add paratoluene sulfonic acidmonohydrate (0.44 g, 2.3 mmol). Attach a Dean-Stark trap, and heat thesolution to reflux .for 2 h. Allow the solution to cool to 23 C, thenpour the contents into ½ satd. NaHCO₃ (150 mL) and EtOAc (150 mL).Filter the mixture, and wash the filter cake with EtOAe and CH₂Cl₂.Separate the layers, and further extract the aqueous layer with EtOAc(100 mL) and CH₂Cl₂ (100 mL). Wash the combined organic extracts withbrine, dry over Na₂SO₄, and concentrate Recrystallization fromhexanes/toluene (9:1) followed by MPLC purification of the motherliquors (0 to 25 to 40% EtOAc/hexanes) affords Preparation 30 as aninseparable mixture of diastereomers (7.02 g, 82% over 3 steps). Note:Purification may be considered optional, as ¹H NMR of the crude productis fairly clean. ¹H NMR (CDCl₃) δ 7.30-7.44 (m, 5H), 6.95 (d, J=8.8 Hz,1H), 6.84 (dd, J=8.8, 2.8 Hz, 1H), 6.78 (d, J=2.8 Hz, 1H), 5.03 (s, 2H),3.98 (1,4H), 3.02-3.24 (m, 1H), 2.30-2.90 (inm, 2H), 1.90-2.22 (m.,41.54-1.67 (m, 1H).

To a −78 C solution of Preparation 30 (7.0 g, 19.1 mmol) in THF (80 mL)add potassium hexamethyldisilane (KHMDS) (53 mL, 0.5 M solution intoluene, 26.7 mmol) over 5 min. Add hexamethylphosphoramide (HMPA) (4.64mL, 26.7 mmol) quickly, and stir the solution at −78 C for 25 min. Add asolution of N-phenyl triflamide (1.5 g, 32.2 mmol) in THF (15 mL+rinse)via syringe. Maintain the resulting solution at −78 C for 2 h, then pourthe reaction contents into ½ satd. NaHCO₃ and extract with Et₂O (150 mL)and EtOAc (2×75 mL). Wash the combined organic extracts with H₂O (2×100mL) and brine (100 mL), dry over Na₂SO₄, and concentrate. Purificationof the crude product by MPLC (0 to 12 to 25% EtOAc/hexanes) affordsPreparation 31 (6.25 g, 66%) as an off-white solid. ¹H NMR (CDCl₃) δ7.25-7.43 (m, 5H), 6.84 (d, J=8.8 Hz, 1H), 6.80 (dd, J=8.8, 2.8 Hz, 1H),6.72 (d, J=2.8 Hz, 1H), 5.02 (s, 2H), 4.04 (1,4H); 3.82 (dd, J=4.4,1.2.8 Hz, 1H), 2.66 (dq, J=14.0, 2.4 Hz, 1H), 2.21 (m, 2H), 1.91 (m,1H), 1.80 (t, J=12.8 Hz, 1H), 1.64 (td, J=12.8, 4.4 Hz, 1H).

Preparation 32

Sparge N₂ (g) through a solution of Preparation 31 (3.0 g, 6.0 mmol),p-benzyloxyphenylboronic acid (1.65 g, 9.0 mmol), and LiCl (0.77 g, 18.1mmol) in DME (40 mL) and aqueous Na₂ CO₃ (7.5 mL, 2 M in H₂O, 15 mmol)for 15 main. Add palladium tetrakis triphenylphosphine (0.69 g, 0.60mmol), then heat the solution to reflux for 24 h, during which time theproduct precipitates out as a white solid. Allow the solution to cool to23 C, then pour the contents into ½ satd NaHCO₃/Et₂O and filter. Washthe filter cake with H₂O and cold Et₂O, affording 2.0 g of Preparation32. Extract the filtrate with EtOAc (3×50 mL) and dry the combinedorganic extracts over Na₂SO₄ and concentrate to afford the remainingcrude product. Purification of the crude material by silica gelchromatography (CH₂Cl₂) affords another 1.04 g. of Preparation 32. Thetotal yield is 3.04 g (95%). ¹H NMR (CDCl₃) δ 7.31-7.47 (m, 12H), 7.01(d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 5.11(s, 2H), 5.03 (s, 2H), 3.98-4.12 (m, 4H), 3.74 (dd, J=12.8, 4.2 Hz, 1H),2,58 (m, 1H), 2,24 (m, 1H), 2.14 (td, J=12.8, 4.2 Hz, 1H), 1.85 (t,J=12.8 Hz, 2H), 1.58 (m, 1H).

Preparation 33

To a mixture of 10 wt % Pd on carbon (0.5 g) in MeOH (100 mL) add aslightly soluble solution of Preparation 32 (3.0 g, 5.63 mmol) in THF(25 mL). Heat the solution to 40 C and maintain under 60 psi of 1-2 (g)for 4 h. Filter the solution and concentrate the filtrate to affordPreparation 33 (−1.8 g crude, -quantitative) as a white solid. ¹H NMR(CD₃OD) δ 7.22 (d, J=8.8 Hz, 2H), 6.77 (m, 3H), 6.66 (d, J=8.8 Hz, 1H),6.53 (dd, J=3.2, 8.8 Hz, 1H), 4.98 (s, 1H), 3.88 (m, 1H), 3.76 (m, 2H),3.68 (m, 1H), 3.47 (m, 1H), 2.48 (d, J=14.8 Hz, 1H), 1.99 (m, 1H), 1.88(dd, J=14.8, 6.0 Hz, 1H), 1.49-1.61 (m, 2H), 1.37-1.46 (m, 1H), 1.27 (m,1H), 1.17 (t, J=7.2 Hz, 3H).

Example 19 Preparation of(6S,6aR,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6,6a,7,8,10,10a-hexahydro-benzo[c]chromen-9-one

(6S,6aR,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6,6a,7,8,10,10a-hexahydro-benzo[c]chromen-9-one

To a solution of Preparation 33 (˜1.7 g crude) in THF (40 mL) and H₂O (1mL) add HCl solution (6 mL, 3 N in H₂O), and stir the mixture overnight.Pour the mixture into satd. NaHCO₃ and extract with Et₂O (2×50 mL) andEtOAc (2×50 mL). Wash the combined organic extracts with brine, dry overNa₂SO₄, and concentrate to afford Example 19 (˜1.3 g, ˜quantitative) asa light yellow solid. This material is of suitable purity to be usedcrude for analogue development, but can be recrystallized from a varietyof solvents (toluene/MeOH/hexanes or iPrOH/hexanes) forcharacterization. ¹H NMR (CD₃OD) δ 7.31 (d: J=8.8 Hz, 2H), 6.85 (d,J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.62 (dd, J=8.8, 2.4 Hz, 1H),5.25 (s, 1H), 3.89 (m, 1H), 2.98 (m, 2H), 2.58 (m, 1H), 2.38 (m, 1H),2.13 (br d, J=14.4 Hz, 1H), 1.66 (m, 2H).

Preparation 34

2-(tert-Butyl-dimethyl-silanyloxy)-6-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]6,6a,7,8,10,10a-hexahydro-benzo[c]chromen-9-one

To a solution of Example 19 (0.120 g, 0.39 mmol) and imidazole (0.079 g,1.16 mmol.) in DMF (2.5 mL) add tert-butyldimethylsilyl chloride (0.131g, 0.87 mmol). Allow the reaction to stir for 1 h, then pour into ½satd. NaHCO₃ (50 mL) and extract with Et₂O (2×25 mL) and EtOAc (25 mL).Wash the combined organic extracts with H₂O (2×25 mL) and brine (25 mL),and dry the organics over Na₂SO₄. Concentrate the mixture, and purifythe residue by MPLC (0% 10% 10% to 20% EtOAc/hexanes) to affordPreparation 34 (0.184g, 88%) as a white solid. ¹H NMR (CDCl₃) δ7.30 (d,J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.8 Hz, 1H), 6.74 (d,=2.8 Hz, 1H), 6.63 (dd, J=8.8, 2.8 Hz, 1H), 5.27 (s, 1H), 3.85 (m, 1H),3.01 (d, J=15.2 Hz, 1H), 2.79 (dd, J=5.8, 15.2 Hz, 1H), 2.45 (m, 1H),2.22 (m, 2H), 1.60-1.80 (m, 2H), 1.01 (s, 9H), 0.99 (s, 9H), 0.23 (s,6H), 0.21 (s, 3H), 0.19 (s, 3H).

Preparation 352-Methoxymethoxy-6-(4-methoxymethoxy-phenyl)-6,6a,7,8,10,10a-hexahydro-benzo[c]chromen-9-one

To a 0 C solution of Example 19 (0.100 g, 0.32 mmol) in THF (3 mL) addpotassium tert-butoxide (0.090 g, 0.81 mmol) followed by methoxymethylchloride (MOM-CI) (0.061 mL, 0.81 mmol). Remove the ice bath and stirfor 1 h at room temperature. Pour the contents into ½ satd. NaHCO₃ (50mL) and extract with Et₂O (2×mL) and EtOAc (2×25 mL). Wash the combineorganic extracts with brine (50 mL.), dry over Na₂SO₄, and concentrateto afford a brown residue. Purify the residue by MPLC (0% to 25% to 50%EtOAchexanes) to afford Preparation 35 (0.102 g, 80%). ¹H NMR (CDCl₃) δ7.37 (d, J=8.4 Hz, 2H), 7.09 (d, -8.4 Hz, 2H) 6.96 (d, d=2.4 Hz, 1H),6.87 (dd, J=2.4, 8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.28 (s, 1H), 5.20(s, 2H), 5.13 (A of AB, J_(AB)7.0 Hz, 1H), 5.07 (B of AB, J_(AB)=7.0 Hz,1H), 3.87 (m, 1H), 3.50 (s, 3H), 3.48 (s, 3H), 3.04 (br d, J=14.4 Hz,1H), 2.79 (dd, J=6.2, 14.4 Hz, 1H), 2.46 (m, 1H), 2.21 (m, 2H),1.62-1.79 (m, 2H).

Preparation 362-(tert-Butyl-dimethyl-silanyloxy)-6-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene

To a −40 C solution of Preparation 34 (0.100 g, 0.19 mmol) in THE (2 mL)and pyridine (0.045 mL) add the Tebbe reagent (Cp₂ ZrCl(H)Me) (0.74 mL,0.5 M toluene, 0.37 mmol). Maintain the reaction at −40 C for 1 h, thenpour the contents into ½ satd. NaHCO₃ (50 mL) and extract with Et₂O(2×25 mL) and EtOAc (2×25 mL.). Wash the combine organic extracts withbrine (50 mL): dry over Na₃SO₄, and concentrate to afford a brownresidue. Purify the residue by MPLC (0% to 5% to 10% EtOAc/hexanes) toafford Preparation 36 (0.093 g, 93%). ¹H NMR (CDCl₃) 7.27 (d, J=8.4 Hz,2H), 6.85 (d, J=8.4 Hz, 2H), 6,75 (m, 2H), 6,61 (dd, J=2.4, 8.8 Hz, 1H),5.15 (s, 1H), 4.62 (m, 2H), 3.49 (br s, 1H), 2.91 (d, .J=14.41 Hz. 1H),2.51 (dd, J=14.4, 4.6 Hz, 1H), 2,15 (m, 2H), 1.92 (td, J=12.8, 5.6 Hz,1H), 1.33 (m, 2H), 1.01 (s, 18H), 0.22 (s, 6H), 0.19 (s, 3H), 0.18 (s,3H).

Example 20 Preparation of(6aR,6S,10aS)-6-(4-Hydroxy-phenyl)-9-dimethylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol

(6aR,6S,10aS)-6-(4-Hydroxy-phenyl)-9-methylene-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol

To a 0 C solution of Preparation 36 (0.093 g, 0.17 mmol) in THF (5 mL)add a solution of tetra-n-butyl ammonium fluoride (0.43 mL, 1 M in THF,0.43 mmol). Stir the solution at 0 C for 1 h, then pour the contentsinto ½ satd. NaHCO₃ (50 mL) and extract with Et₂O (2×25 mL) and EtOAc(2×25 mL). Wash the combine organic extracts with brine (50 mL), dryover Na₂SO₄, and concentrate to afford a brown residue. Purify theresidue by MPLC (0% to 25% to 40% EtOAc/hexanes) to afford Example 22(0.028 g, 52%) as a white solid. ¹H NMR (CD₃OD) δ 7.26 (d, J=8.8 Hz,2H), 6.82 (d, J=8.8 Hz, 2H), 6.79 (d, J -3.2 Hz, 1H): 6.69 (d, J=8.4 Hz,1H), 6.57 (dd, J=3.2, 8.4 Hz, 1H), 5.09 (s, 1H), 4.62 (m, 1H), 3.48 (s,1H), 2.97 (d, J=13.6 Hz, 1H), 2.54 (dd, J=5.2, 13.6 Hz, 1H), 2.17 (m,2H), 1.95 (dd, J=5.2, 12.8 Hz, 1H), 1.25-1.38 (m, 2H).

Example 2 Preparation of(6aR,6S,9S,10aS)-6-(4-Hydroxy-phenyl-9-methyl-6a7,9,10,10a-hexahydro-6H-benzo[c]chromen-2-oland(6aR,6S,9R,10aS)-6-(4-Hydroxy-phenyl)-9-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol

(6aR,6S,9S,10aS)-6-(4-Hydroxy-phenyl)-9-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-oland(6aR,6S,9R,10aS)-6-(4-Hydroxy-phenyl)-9-methyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol

To a mixture of 10 wt % Pd on carbon (0.03 g) in MeOH (20 mL) add asolution of Example 22 (0.022 g, 0.07 mmol) in MeOH (2 mL). Maintain thesolution under 60 psi of H₂ (g) for 4 h. Filter the solution andconcentrate the filtrate to afford Example 23 (0.022 g crude, 100%) as3:1 ratio of epimers as a white solid. Major diastereomer: ¹ NMR (CD₃OD)δ 7.22 (d, J=8.4 Hz, 2H), 6.81 (d, J -2.4 Hz, 1H), 6.78 (d, J=8.4 Hz,2H), 6.68 (d, J=8.8 Hz, 1H), 6.54 (dd, J=8.8, 2.4 Hz, 1H), 4.94 (s, 1H),3.30 (m, 1H), 2.23 (d, J=13.6 Hz, 1H), 1.95 (m, 2H), 1.33-1.56 (m, 3H),1.20 (m, 1H), 1.11 (m, 1H), 0,63 (d, J=7.2 Hz, 3H).

Preparation 37

9,9-Difluoro-2-methoxymethoxy-6-(4-methoxymethoxy-phenyl)-6a-7,8,9,10,10a-hexahydro-6H-benzo[c]chromene

Heat a mixture of Preparation 35 (0.102 g, 0.26 mmol) and (Diethylamino)sulfur trifluoride (0.25 mL) in 1,2-dichloroethane (0.75 mL) to 40 C for12 h. Purify the mixture by MPLC (0% to 10% to 25% EtOAc/hexanes) toafford Preparation 37 (0.042 g, 39%). ¹H NMR (CDCl₃) δ 7.35 (d, J=8.8Hz, 2H), 7.08 (d J=8.8 Hz, 2H), 7.02 (s, 1H), 6.86 (m, 2H), 5.20 (s,2H), 5.16 (s, 1H), 5.15 (A of AB, J_(AB)=6.4 Hz, 1H), 5.11 (B of AB,J_(AB)=6.4 Hz, 1H), 3.66 (br s, 1H), 3.50 (s, 6H), 2.84 (m, 1H),1.96-2.23 (m, 3H), 1.54-1.69 (m, 2H), 1.44 (m, 1H).

Example 22 Preparation of6aR,6S,10aS)-9,9-Difluoro-6-(4-hydroxy-phenyl)-6a,7,89,10,10a-hexahydro-6-benzo[c]chromen-2-ol

(6aR,6S,10aS)-9,9-Difluoro-6-(4-hydroxy-phenyl)-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-2-ol

Add a solution of HCl (2 mL, 3 N in H₂O) to Preparation 37 (0.042 g,0.10 mmol) in THF (5 mL) and H₂O (1 mL) and stir the mixture for 12 h.Pour the mixture into satd. NaHCO₃ and extract with Et₂O (2×50 mL) andEtOAc (2×50 mL). Wash the combined organic extracts with brine, dry overNa₂SO₄, and concentrate to afford the desired product as a light yellowsolid. Purify the crude material by MPLC (0% to 25% to 40%EtOAc/hexanes) to afford Example 24 (0.014g, 37%) as a yellow oil. ¹HNMR (CD₃OD) δ 7.25 (d. J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 6.79 (d,J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.56 (dd, J=2.4 Hz, 1H), 5.07 (s,1H), 3.62 (br s, 1H), 2.77 (m, 1H), 2.09-2.28 (m, 2H), 1.90 (m, 1H),1.47-1.65 (m, 2H), 1.36 (m, 1H).

Preparation 38 4-Allyl-6-benzyloxy-2-oxo-chroman-3-carboxylic acid ethylester

To a 0 C solution of Preparation 27 (10.0 g, 30.8 mmol) in THF (125 mL)add a solution of allyl magnesium chloride in Et₂O (46 mL, 1.0 M, 46mmol). Maintain the reaction at 0 C for 30 min, then pour the reactioncontents into. a solution of ½ satd, NaHCO₃ (250 mL). Extract thesolution with Et₂O (2×150 mL) and EtOAc (150 mL). Wash the combinedorganic extracts with 120 (150 mL) and brine (150 mL), dry the organicsover Na₂SO₄, and concentrate to afford a brown oil. Purify the productby MPLC (0% to 15% to 25% EtOAc/hexanes) to afford Preparation 38 (7.72g, 68%) as a light yellow solid. ¹H NMR (CDCl₃) δ 7.31-7.43 (m, 5H),7.01 (d, J=8.8 Hz, 1H), 6.87 (dd, J=8.8, 3.0 Hz, 1H), 6.79 (d, J=3.0 Hz,1H), 5.71 (m, 1H), 5.15 (dd, J=0.8, 9.8 Hz, 1H), 5.10 (dd, J=0.8, 17.6Hz, 1H), 504 (A of AB, J_(AB)=14.2Hz, 1H), 5.03 (B of AB, J_(AB)=14.2Hz, 1H), 4.08 (m, 2H), 3.80 (d, J=2.4 Hz, 1H), 3.41 (m, 1H), 2.35 (m,2H), 1.08 (t, J=7.2 Hz, 3H).

Preparation 39 4-Allyl-6-benzyloxy-chroman-2-one

Heat a solution of Preparation 38 (4.8 g, 13.1 mmol) and LiOH (6 g) in asolution of THF (75 mL), EtOH (30 mL), MeOH (20 mL), and H₂O (50 mL) to60 C for 2 h, Pour the contents into 1 N HCl (250 mL) and extract themixture with Et₂O (2×200 mL) and EtOAc (2×150 mL). Wash the combinedorganic extracts with brine (200 mL), dry over Na₂SO₄, and concentrateto afford the crude β-keto acid.

Heat a solution of the crude acid in o-xylenes to reflux for 1.5 h,Remove the solvent in vacuo, and purify the lactone by MPLC (0% to 12%to 20% EtOAc/hexanes) to afford Preparation 39 (3.5 g. 91%) as a whitesolid. ¹H NMR (CDCl₃) δ 7.31-7.44 (m, 5H), 6.99 (d, J=8.8 Hz, 1H), 6.86(dd, J=8.8, 3.2 Hz, 1H), 6.81 (d, J=3.2 Hz, 1H), 5.72 (m, 1H), 5.07-5.14(m, 2H), 5.05 (s, 2H), 3.03 (m, 1H), 2.76 (t, J=8.8 Hz, 2H), 2.43 (m,1H), 2.30 (m, 1H).

Preparation 404-Allyl-6-benzyloxy-3-(2-methoxymethoxy-allyl)-chroman-2-one

Cool a solution of Preparation 39 (3.65 g, 12.4 mmol) in THF (90 mL) to−78 C. Add a solution of KHMDS (32 mL, 0.5 M in toluene, 16 mmol.) over5 min, then allow to stir for 15 in at −78 C. Addhexamethylphosphoramide (HMPA) via syringe (2.8 mL, 16.1 mmol.) quickly,and allow to stir for 20 min at −78 C. Add 2-O-methoxylmethyl allyliodide (4.24 g) over 2 min, and then allow the solution to warm to −50 Cover 1.5 h. Pour the contents of tire reaction into 2 satd. NaHCO₃ andextract with Et₂O (2×100 mL) and EtOAc (2×100 mL). Wash the combinedorganic extracts with H₂O (2×150 mL) and brine (150 mL) and then dryover Na₂SO₄. Concentrate the crude product to leave a brown oil, whichis purified by MPLC (0% to 12% to 20% EtOAc/hexanes) to affordPreparation 40 (3.72 g, 76%) as a light yellow oil. ¹H NMR (CDCl₃) δ7.31-7.44 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (dd, J=8.8, 3.2 Hz, 1H),6.74 (d, J=3.2 Hz, 1H), 5.66 (m, 1H), 5.01-5.09 (m, 4H), 41.93 (A ob AB,J_(AB)=6.4 Hz, 1H), 4.90 (B of AB, J_(AB)=6.4 Hz, 1H), 4.18 (d, J=2.4Hz, 1H), 3.87 (d, J=2A Hz, 1H), 3.44 (s, 3H), 3.18 (m, 1H), 2.86 (m,1H), 2.22-2.39 (m, 3H), 2.12 (dd, J=9.4, 14.0 Hz, 1H).

Preparation 412-Benzyloxy-8-methoxymethoxy-6a,7,10,10a-tetrahydro-benzo[c]chromnen-6-one

Bubble N2 gas through a solution of Preparation 40 (1.0 g, 2.54 mmol) inCH₂Cl₂ (250 mL) equipped with a reflux condenser for 30 min. Add[1,3-bis-(2,4,6-.trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-tricyclohexylphosphine)ruthenium](0.212g, 0.25 mmol) and heat the reaction to reflux for 2.5 h. Allow thereaction to cool to room temperature, remove the condenser, and bubbleair through the mixture for 10 min. Remove the solvent in vacuo, andpurify the residue by MPLC (0% to 12% to 25% EtOAc/hexanes) to affordPreparation 41 (0.72 gm, 78%) as a clear oil. ¹H NMR (CDCs₃) δ 7.32-7.45(m, 5H), 7.00 (d, J=8.4 Hz, 1H), 6.86 (m, 2H), 5.05 (m, 3H), 5.00 (A ofAB, J_(AB)=6.4 Hz, 1H), 4.97 (B of AB, J_(AB)=6.4 Hz, 1H), 3.45 (s, 3H),2.94 (im, 1H), 2.83 (m, 1H), 2.56-2.70 (m, 3H), 2.25 (m, 1H).

Preparation 42

Treat a solution of Preparation 41 (0.72 g, 1.97 mmol) in THF.(40 mL)with 3 N HCl (3 mL) for 4 h. Pour the contents into H₂O and extract withEt₂O and EtOAc. Wash the combined organic extracts with satd. NaHCO₃ andbrine, dry the combined extracts over Na₂SO₄, and concentrate to affordthe crude intermediate ketone. Dissolve the ketone in toluene (40 mL)and add p-toluenesulfonic acid monohydrate (0.038 g), then attach a DeanStark apparatus and heat the reaction to reflux for 2.5 h. Pour thecontents into ½ satd. NaHCO₃ (50 mL) and separate the layers. Furtherextract the aqueous layer with Et2O and EtOAc (50 mL each). Wash thecombined organic extracts with brine (50 mL), dry the combined organicsover Na2SO4, and concentrate to afford Preparation 42 (0.74 g, 100%) asa white solid. #H NMR (CDCl₃) δ 7.31-7.44 (m, 5H), 6.98 (d, J=8.4 Hz,1H), 6.86 (m, 2H), 5.04 (s, 2H), 4.03 (m, 2H), 3.94 (m, 2H), 2.71 (m,1H), 2.55 (m, 1H), 2.35-2.46 (m, 2H), 1.92 (m, 1H), 1.67-1.79 (m, 3H).

Preparation 43

To a −78 C solution of Preparation 42 (0.366 g, 1.0 mmol) in THF (8 mL)add a solution of LDA (1.13 mL, 1.5 M cyclohexane, 1.7 mmol). Stir at−78 C for 15 min, then add HMPA (0.59 mL, 3.4 mmoL) and warm to −50 C.Stir for 15 min, then recool the solution to −78 C. Add a solution ofN-phenyl triflamide (0.607 g, 1.7 mmol) in THF (2 mL) dropwise, and stirthe resulting solution for 30 min. Pour the reaction contents into ½satd. NaHCO₃, and extract the mixture with Et₂O (2×30 mL) and EtOAc (40mL). Wash the combined organic extracts with H₂O (2×50 mL) and brine (50mL), dry the organic layer over Na₂SO₄, and concentrate to afford thecrude product. Purify the material by MPLC (0% to 15% to 25%EtOAc/hexanes) to afford Preparation 43 (0.059 g, 12%) as a yellow oil.¹H NMR (CDCl₃) δ 7.28-7.43 (m, 5 H), 6.81 (m, 2H), 6.75 (d, J=2.4 Hz,1H), 5.02 (s, 2H), 3.99 (m, 4H), 3.51 (q, J=5.2 Hz, 1H), 2.73 (dd,J=2.8, 14.0 Hz, 1H), 2.17 (m, 2H), 1.83-1.97 (m, 3H).

Preparation 44

Sparge N₂ (g) through a solution of Preparation 43 (0.059 g, 0.12 mmol),p-benzyloxyphenylboronic acid (0.038 g, 0.165 mmol), and LiCl (0.025 g,0.60 mmol) in DME (2.5 mL) and aqueous Na₂ CO₃ (0.25 mL, 2 M in H₂O, 0.5mmol) for 15 min. Add palladium tetrakis triphenylphosphine (0.035 g,0.03 mmol.) and heat the solution to reflux for 24 h. Allow the solutionto cool to 23 C, then pour the reaction contents into ½ satd NaHCO₃, andextract with EtOAc (3×25 mL). Combine the organic extracts and wash withbrine (25 mL), then dry over Na₂SO₄ and concentrate. Purify the residueby MPLC (0% to 12% to 25% EtOAc/hexanes) to afford Preparation 44(0.024g, 38%) as a clear oil. ¹H NMR (CDCl₃) δ 7.31-7.47 (m, 10H), 7.01(d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.79 (s, 1H), 6.75 (d, J=8.8Hz, 2H), 5.11 (s, 2H), 5.04 (s, 2H), 3.97 (m, 4H), 3.43 (m, 1H), 2.64(dd, J=2.8, 14.0 Hz, 1H), 2.20 (m, 1H), 2.13 (m, 1H), 1.99 (m, 1H), 1.91(m, 2H).

Preparation 45

To a mixture of 10 wt % Pd on carbon (0.02 g) in MeOH (25 mL) add asolution of Preparation 44 (0.020g, 0.04 mmol) in THF (10 mL). Maintainthe solution under 60 psi of H₂ (g) for 4 h. Filter the solution andconcentrate the filtrate to afford Preparation 45 (0.012 g crude,˜quantitative) as a white solid. TLC R_(f) 0.4, 60% EtOAc/hexanes.

Example 23 Preparation of(6aR,6S,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6a,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one

(6aR,6S,10aS)-2-Hydroxy-6-(4-hydroxy-phenyl)-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one

To a solution of Preparation 45 (0.012 g) in THF (20 mL) and H₂O (1 mL)add HC solution (2 mL, 3 N in H₂O), and stir the mixture overnight. Pourthe mixture into satd. NaHCO₃ and extract with Et₂O (2×50 mL) and EtOAc(2×50 mL). Wash the combined organic extracts with brine, dry overNa₂SO₄, and concentrate to afford crude Preparation 27 as a light yellowsolid. Purify the crude material by MPLC (0% to 25% to 50%EtOAc/hexanes) to afford Example 25 (0.010g, 90%) as a white solid. ¹HNMR (CD₃OD) δ 7.22 (d, J=8.0 Hz, 2H), 6.85 (m, 1H), 6,79 (min, 3), 6.64(m, 1H), 5.22 (s, 1H), 3.54 (m, 1H), 2.67 (m, 1H), 2.56 (m, 1H), 2.26(m, 2H), 2.13 (1,2H), 1.84 (dd, J=3.9, 14.5 Hz, 1H).

Preparation 46 6-Benzyloxy-chromen-2-one

Equip a 5-L, three-neck, round-bottom flask with a large blademechanical stirrer, thermocouple, an addition funnel, Claisen adapter,reflux condenser, and a sodium hydroxide scrubber. Charge the flask with2,5-dimethoxycinnamic acid (182.3 g, 865 mmol, 1.0 equiv) anddichloroethane (2.5 L). Add boron tribromide (163.5 mL, 433.2 g, 1.73mol, 2.0 equiv.) dropwise over 1 h, keeping the temperature below 35° C.Gas evolution can be monitored as the temperature of the reaction isgradually increased to reflux (82° C.). Reflux for 1.2 h, cool to 5° C.,and quench by the careful addition of water (1.0 L). Filter theresulting yellow-red suspension/emulsion through a glass frit and washwith dichloroethane (1.0 L) and heptane (1.0 L) to afford a brown solid.Dry the wet material in a vacuum oven (30 in., 35° C.) for 18 h, toafford the coumarin (180.3 g, 127% theory) as a brown solid: ¹H NMR (300MHz, DMSO-d₆) δ 7.97 (d, J=9.6 Hz, 1H), 7.22. (d, J=9.9 Hz, 1H), 7.05(m, 2H), 6.43 (d, J=9.6 Hz, 1H).

Equip a 5-L, three-neck, round-bottom flask with a mechanical stirrer,thermocouple, an addition funnel, and an inlet adapter. Charge the flaskwith the coumarin prepared above (360.0 g, 2.20 mol, 1.0 equiv) andN,N-dimethylformamide (2.2 L). While keeping the temperature below 30°C., add cesium carbonate [904.2 g, 2.78 mol, 1.25 equiv]. Then addbenzyl bromide [475.5 g, 330.2 mL, 2.78 mol, 1.25 equiv]over a period of1 h, keeping the temperature below 35° C. during the addition. Stir themixture at ambient temperature (25-30° C.) for 10.5 h. Four the reactionmixture into ice water (4.5 L), filter, and dry at ambient pressure for72 h, triturate in heptane (1.5 L) with vigorous stirring, filter, anddry under reduced pressure (30 in., 35° C.) to afford preparation 46(302.4 g, 1.20 mol, 60%) as a light brown solid: ¹H NMR (300 MHz,DMSO-d₆) 7.99 (d, J=9.6 Hz, 1H), 7.50-7.29 (m, 8H, 6.49 (d, J=9.5 Hz,1H): 5.15 (s, 2H); ¹³NMR (75 MHz, DMSO-d₆) δ 160.0, 154.6, 147.9, 143.9,136.6, 128.4, 127.9, 127.7, 119.9, 119.1, 117.3, 116.6, 111.9, 69.8; IR(KBr) 3052 (w), 1708 (s), 1568 (m), 1492 (w), 1444 (w), 1383 (w), 1272(m), 1168 (w), 1110 (i), 1020 (m), 927 (w), 814 (w), 762 (w), 709 (w)cm⁻¹; HPLC analysis 95.9% (AUC), Phenomenex Luna C18(2) column; ESI MSm/z 253 [C₁₆H₁₂O₃+H]⁺

Preparation 478-Benzyloxy-2-methylene-2,3,3a,9b-tetrahydro-1H-cyclopenta[c]chromen-4-one

Starting from preparation 46 this compound can be prepared in a mannersubstantially similar to that described in preparation 13. ¹H NMR (400MHz, CDCl₃) δ 7.44-7.32 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 6.86 (dd,J=3.1, 8.8 Hz, 1H), 6.82 (d, J=3.1 Hz, 1H), 5.04 (s, 2H), 4.98-4.95 (m,2H), 3.40 (dt, J=7.5, 16.3 Hz, 1H), 3.15 (ddd, J=4.4, 7.9, 11.9 1H),3.06-3.01 (m, 1H), 2.82-2.72 (m, 2H), 2.47-2.40 (m, 1H).

Preparation 488-Benzyloxy-4-(4-benzyloxy-phenyl)-2-methylene-1,2,3,9b-tetrahydro-cyclopenta[c]chromene

Add p-benzyloxybromobenzene (20 g, 76 mmol) to magnesium metal (1.85 g,76 mmol). Plush with nitrogen and add 76 mL of TH-F followed by a smallcrystal of I₂. Heat to reflux to initiate Grignard formation and thenlet stir at room temperature overnight. Add the resulting aryl Grignardvia cannula to a solution of ZnCl₂ (76 mL of a 1 M solution in Et₂O, 76mmol) in 1.52 mL of THF. Stir for 30 min and then let the precipitatesettle to give a solution of the aryl zinc.

Cool a solution of preparation 47 (9.43 g, 30.8 mmol) in 312 mL of THFto −78° C. Add KHMDS (74 mL of a 0.5 M solution in toluene, 37 mmol).Stir for 20 min. Add via cannula a solution of N-phenylbis(trifluoromethanesulphonamide) (13.22 g, 37 mmol) in 47 mL of THF.Stir for 2 hrs and then quench with saturated aqueous NH₄ Cl. Partitionthe solution between 250 mL of 1:1 water:brine and 250 mL of EtOAc.Separate and wash the organic solution with brine, dry over Na₂SO₄,filter, and concentrate. Adsorb the material to silica gel and purify bysilica gel chromatography eluting with a linear gradient of 0-100%CH₂Cl₂ in hexanes to afford 9.77 g (22.3 mmol, 72%) of the enol triflateof preparation 46.

Add via cannula the solution of the aryl zinc described above to asolution of the enol triflate described above and Pd(PPh₃) (2.57 g, 2.22mmol) in 36 mL of THF under N₂. Heat the solution to 50° C. for 30 main.Cool the solution to room temperature and quench with saturated aqueoussodium bicarbonate and extract with EtOAc. Wash the combined organicsolutions with brine, dry over Na₂SO₄, filter and concentrate. To removethe catalyst, dissolve the residue in 1:1 hexanes:CH₂Cl₂ and filterthrough celite. Further purify the product by filtration through silicagel using 1:1 hexanes:CHC₂. Further purify by re-crystallization fromEtOAc and hexanes to afford 5.96 g (12.6 mmol, 57%) of preparation 48,¹H NMR (4.00 MHz, CDCl₃) δ 7.58-7.38 (m, 12H), 7.06-7.03 (m, 31), 6.87(dd, J=2.6, 8.8 Hz, 1), 6.79 (d, J=3.1 Hz, 1H), 5.15 (s, 2H), 5.09 (s,2H), 5.06 (s, 1H), 5.00 (a, 1H), 3,95 (t, J=9.7 Hz, 1H), 3.48 (d, J=20Hz, H), 3.33 (d, J=20 Hz, 1H), 3.12 (dd, J=8.4, 15.4 Hz 1H), 2.50 (t,J==12.8 Hz, 1H).

Preparation 498-Benzyloxy-4-(4-benzyloxy-phenyl)-2-methylene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Add TFA (3.2 mL, 41.6 mmol) to a solution of preparation 48 (5.94 g,12.6 mmol) and Et₃SiH (20.1 mL, 126 mmol) in 101 mL of Cl₂Cl₂ at 0° C.Stir for 5 min and then pour into a solution of saturated aqueous sodiumbicarbonate. Wash the organic solution two times with saturated aqueoussodium bicarbonate, dry over Na₂SO₄, filter, and concentrate. Purify theproduct by silica gel chromatography eluting with 10-60% Ch₂ Cl₂ inhexanes to afford 3.67 g (7.73 mmol, 62%) of preparation 49. ¹H NMR (400MHz, CDCl₃) δ 7.50-735 (m, 12H ), 7.29-7.02 (m, 2H), 6.88 (d, J=9.2 Hz,1H), 6.83-6.79 (m, 2H), 5.14 (d, J=1.8 Hz, 1H), 5.12 (s, 2H), 5.05 (s,2H), 4.78 (m, 2H), 3.60 (t, J=7.5 Hz, 1H), 2.92 (m, 1H), 2.73 (m, 1H),2.65 (d, J=16.7 Hz, 1H), 2.46 (m, 1H), 2.13 (dd, J=7.9, 16.7 Hz, 1Ht).

Preparation 508-Benzyloxy-4-(4-benzyloxy-phenyl)-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one

Add osmium tetroxide (4.8 mL of a 2.5 wt % solution in t-BuOH, 0.38mmol) to a solution of preparation 49 (3.62 g, 7.63 mmol),N-methylmorpholine (0.84 mL, 7.6 mmol), and N-methylmorpholine-N-oxide(1.79 g, 15.3 mmol) in 55 mL of THF and 21 mL of water. Stir for 6.5 hrsand then add 88 mL of THF, 106 mL of water and sodium periodate (8.16 g,38.2 mmol). Stir overnight. Quench with an 1:1 solution of saturatedaqueous Na₂SO₃ and saturated aqueous NaHCO₃. Separate the organicsolution and wash with brine, dry over Na₂SO₄, filter and concentrate.Dissolve in 1:1 EtOAc:CH₂Cl₂ and wash with water, dry over Na₂SO₄,filter and concentrate to afford 3.35 g (7.03 mmol, 92%) of preparation50. ¹H NMR (400 MHz, CDCl₃) 7.49-7.34 (m, 12H), 7.04-7.02 (m, 2H), 6.92(d, J=8.8 Hz, 1H), 6.85 (dd, J=2.6, 8.8 Hz, 1H), 6.77 (d, J=2.6H), 5.16(s, 1H), 5.12 (s, 2H), 5.04 (s, 21), 3.90 (t, J=7.5 Hz, 1H), 2.96 (dt,J=3.0, 13.7 Hz, 1H), 2.80 (dd, J=8.4, 18.5 Hz, 1H), 2.63 (d, J=18.1 Hz,1H), 2.37 (dd, J=11.9, 18.9 Hz, 1H), 2.08 (dd, J=7.9, 18.5 Hz, 1H).

Preparation 518-benzyloxy-4-(4-(4-benzyloxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-ol

Add sodium borohydride (240 mg, 6.3 mmol) to a solution of preparation50 (1.5 g, 3.15 mmol) in 30 mL of THF and 30 mL of methanol, Let stirfor 30 min. Quench with saturated aqueous ammonium chloride, separate,back extract the aqueous solution two times with EtOAc. Combine theorganic solutions and wash with 1:1 brine:water, dry over Na₂SO₄,filter, and concentrate to give 1.5 g (3.13 mmo, 99%) of preparation 51.¹H NMR (400 MHz, CDCl₃): δ 7.56-7.33 (m, 12H), 7.05-7.01 (m, 2H), 6.92(d, J=8.8 Hz, 1H), 6.83-6.80 (m, 21H), 5.12 (s, 2H), 5.07 (s, 1H), 5.06(s, 21). 4.27 (d, J=6.6, 11.0 Hz, 1H), 3.53 (m, 1H), 2.63 (m, 1H), 2.51(dt, J=7.5, 13.6 Hz, 1H), 1.92-1.86 (m. 2H), 1.72 (dddd, J=6.6, 11.0,13.6, 17.1 Hz, 1H). HRMS (ES+) calc: 496.2488; found: 496.2485 [M+NH₄]⁺.

Preparation 528-Benzyloxy-4-(4-benzyloxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2-carbonitrile

To a solution of preparation 51 (50 mg, 0.104 mmol), acetone cyanohydrin(48 μL, 0.52 mmol), and triphenyl phosphine (137 mg, 0.52 mmol), in 2.5mL of THF at 0° C. add diisopropylazodicarboxylate (103 μL, 0.52 mmol).Stir the solution and allow it to warm slowly to room temperatureovernight. Add 1 g of silica gel and concentrate, Purify by silica gelchromatography eluting with 10-30% EtOAc in hexanes to afford 30 mg(0.62 mmol, 59%) of preparation 52. ¹H NMR (400 MHz, CDCl₃): δ 7.63-7.33(m, 12H), 7.06-7.02 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 6.83 (dd, J=3.1,8.8 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 5.13 (s, 2H), 5,07 (d, J=2.2 Hz,1H), 5.06 (s, 2H), 3.70 (t, J=6.6 Hz, 1H), 2.97 (ddt, J=2.2, 9.2, 18.9Hz, 1H), 2.68 (m, 1H), 2.43 (m, 1H), 2.28 (ddd, J=1.8, 7.0, 8.8 Hz, 1H),2.15 (dt, J=9.2, 13.6 Hz, 1H), 1.80 (ddd, J=6.2, 9.3, 13.6 Hz, 1H); HRMS(FAB) calcd. for C₃₃H₂₉ NO₃: 487,2147; found: 487.2124 (M+).

Example 24 (2R,3aR,4S,9bS)- and(2S,3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyelopenta[c]chromene-2-carbonitrile

Dissolve preparation 52 (24 mg, 0.050 mmol) in 1 mL of THF. Add a slurryof 10% Pd/C (10 mg) in 1 mL of iPrOH. Add another 1 mL of THF, warm toredissolve preparation 52, then stir under an atmosphere of hydrogen gasat ambient pressure for 6 hrs. Filter the solution through a 0,2 nm HPLCfilter, wash with methanol and concentrate. Purify by silica gelchromatography elating with 5-50% (9:1 EtOAc:MeOH) in hexanes to afford11.2 mg (0.036, 73%) of example 26. ¹H NMR (400 MHz, CDCl₃): δ 7.32-7.30(m, 2H), 6.85-6.82 (m, 2H), 6.76 (d, J=8.4 Hz, 1H), 6.65 (d, J=2.6 Hz,1H), 6.61 (dd, J=3.0, 8.7 Hz, 1H), 5.00 (d, J=2.5 Hz, 1H), 3.67 (t,J=6.6 Hz, 1H), 2.99 (dt, J=22, 9.7 Hz, 1H), 2.72 (ddd, J=7.0, 9.7, 13.6Hz, 1H), 2.41 (ddd, J=7.0, 9.7, 12.7 Hz, 1H), 2.29 (ddd, J=1.6, 6.6, 8,8Hz, 1H), 2.11 (ddd, J=9.2, 13.6, 18.0 Hz, 1H), 1.68 (ddd, J=6.6, 9.2,1.3.2 Hz, 1H). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 minthen 100% CH₃CN for 5 min; 1 mL) min; t_(r) 9.064 mrin). HRMS (ES−)calcd. for C₁₉H₁₆NO₃: 306.1130; found: 306.1.55 (M−1).

Preparation 538-Benzyloxy-4-(4-benzyloxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2-carbonitrile

Place preparation 51 (0.2619 g, 0.5472 mmol) and triphenylphosphine(0.29 g, 1.1 mmol) in a flask and flush with N₂. Add THE (5.5 mL) andp-nitrobenzoic acid (0.27 g 1.6 mmol) and cool to 0° C. Adddiisopropylazodicarboxylate (0.22 mL, 1.1 mmol) dropwise to the reactionmixture keeping it below 5° C. Let the reaction mixture warm slowly toroom temperature overnight overnight. Dilute the solution with EtOAc(100 mL), wash with saturated aqueous sodium bicarbonate (2×50 mL),brine (50 mL), dry over Na₂SO₄, filter and concentrate, Purify by silicagel chromatography (10-25% of 9:1 CH₂Cl₂:EtOAc in hexanes over 30 min)to afford 0.1876 g (0.2989 mmol, 55%) of a yellow solid. ¹H NMR (400MHz, CDCl₃): δ 8.30 (d, 2H, J=8.8 Hz), 8.71 (d, 2H, J=8.8 Hz), 7.35-7.49(m, 10H), 7.41 (d, 2H, J=8.8 Hz), 7.03 (d, 2, J=8.4 Hz), 6.91 (d, 1H,J=8.8 Hz), 6.81-6.85 (m, 2H), 5.41 (m, 1H), 5.14 (m, 1H), 5.11 (s, 2H),5.06 (s, 2H), 3.74-3.77 (m, 1H), 2.95-3.02 (m, 1H), 2.49-2.55 (m, 1H),2.36-2.42 (m, 1H), 2.16-2.24 (m, 1H), 1.73 (dd, 1H, J=7.5 Hz, J=14 Hz),HRMS (CI+) calcd. for C₃₉H₃₃NO₇: 627.2257; found: 627.2263 (M+).

Dissolve the yellow solid (0.1839 g, 0.2930 mmol) in 2.9 mL of THF andadd an aqueous solution of LiOH (0.035 g, 1.5 mmol) in 1.1 mL of water.Stir at room temperature overnight. Add 1.0 M aqueous NaH₂PO₄ (1.5 mL,1.5 mmol). Dilute with EtOAc (100 mL), wash with saturated aqueousNaHCO₃ (2×50 mL), wash with brine (50 mL), dry over Na₂SO₄, filter andconcentrate to afford a white solid (0.1.398 g, 0.2921 mmol, 99%). ¹HNMR (400 MHz, CDCl₃): δ 7.36-7.49 (m, 12H), 7.03 (d, 2H, J=8.8 Hz),6.87-6.89 (m, 114), 6.78-6.80 (m, 2H), 5.12 (s, 21), 5.10-5.11 (m, 1H),5.05 (s, 2H), 4.34 (m, 1H), 3.65-3.70 (m, 1H), 2.98-3.06 (m, 1H),2.26-2.32 (m, 1H), 2.04-2.10 (m, 1H), 1.87-1.95 (m, 1H), 1.44 (dd, 1H, J-7.9 Hz, J=14 Hz), 1.30 (m, 1H). HRMS (CI+) calcd. for C₃₂H₃₀O₄:478.2144; found: 478.2154 (M+).

Dissolve the white solid (0.1092 g, 0.2282 mmol) and PPh₃ (0.30 g, 1,1mmol) in THF (5.5 mL.). Add acetone cyanohydrin (0.42 mL, 4.6 mmol) andcool to 0° C. Add diisopropyl azodicarboxylate (0.22 mL, 1.1 mmol)dropwise keeping the solution below 5° C. Let the solution warm slowlyto room temperature overnight. Add silica gel and concentrate. Purify bysilica gel chromatography eluting with CH₂Cl₂ in EtOAc to afford 0.0432g (0.0886 mmol, 39%) of preparation 53. ¹H NMR (400 MHz, CDCl₃): δ7.35-7.50 (m, 12H), 7.04 (d 21, 0.1, J=8.8 Hz), 6.92 (d, 1H, J=8.8 Hz),6.84 (dd, 1H, J=8.8 Hz, J=3.1 Hz), 6.76 (d, 1H, 1=3.1 Hz), 5.13 (s, 2H),5.06 (s, 2H), 5.05 (m, 1H), 3.59-3.65 (m, 1H), 2.70-2.80 (m, 2H),2.59-2.67 (m, 1H), 2.00-2.10 (m, 2H), 1.84-1.91 (m, 1H). HRMS calcd. forC₃₃H₂₉NO₃: 487.2147; found: 487.2134 (M+).

Example 25 (2S,3aR,4S,9bS)- and(2R,3aS,4R,9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2-carbonitrile

Example 27 can be prepared in a manner substantially similar to Example26 except starting from Preparation 53. The hydrogenation is carried outunder a 60 psi atmosphere of hydrogen for several days. ¹H NMR (8, 400MHz, CDCl₃): 7.30 (d, 2H, J=8.4 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.78 (d,2H, J=8.8 Hz), 6.64-6.56 (m, 1H), 6.62 (dd, 1.H, J=8.4, 2.6 Hz), 4.99(m, 1H), 3.55-3.62 (m, 1H), 2.90-3.00.(m, 1H), 2.67-2,76 (m, 2H),1.94-2.04 (m, 2H), 1.78-1.94 (m, 2H). HPLC (Zorbax C18 column; 10 to100% CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r)8.873 min). HRMS (CI+) calcd, for C₁₉H₁₇ NO₃: 307.1208; found: 307.1212[M+].

Preparation 548-(tert-Butyl-dimethyl-silanyloxy)-4-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one

Dissolve Preparation 50 (1.59 g, 3.33 mmol) in 50 mL of THE Add a slurryof 10% Pd/C (570 mg) in isopropyl alcohol. Stir the solution under 60psi of hydrogen gas overnight. Filter the solution through celite andwash with isopropyl alcohol and THF. Combine and concentrate the organicsolutions to afford a tan solid. Dissolve the solid 17 mL of DMF. Addimidazole (1.36 g, 20 mmol) and DMAP (42 m g, 0.34 mmol) followed byTBSCI (1.10 g, 7.3 mmol); Let the solution stir overnight. Dilute withEtOAc and wash with saturated aqueous sodium bicarbonate, water, brine,dry over Na₂SO₄, filter, and concentrate. Purify by silica gelchromatography eluting with 0-10% EtOAc in hexanes to afford 1.15 g(2.19, 66%) of preparation 54. ¹H NMR (400 MHz, MeOD): δ 7.33-7.30 (m,2H), 6.90-6.87 (m, 2H), 6.85 (d, J=8.8 Hz, 1H), 6.68 (dd, J=2.2, 8.8 Hz,1H), 6.63 (d, J=2.2 Hz, 1H), 5.15 (d, J=1.8 Hz, 1H), 3.87 (t, J=7.5 Hz,1H), 2.93 (m, 1H), 2.81 (dd, J=7.6, 17.6 Hz, 1H), 2.62 (d, J=18.5 Hz,1H), 2.36 (dd, J=12.3, 18.8 Hz, 1H), 2.04 (dd, J=7.9, 18.8 Hz, 1H), 1.02(s, 9H), 1.01 (s, 9H), 0.24 (s, 6H), 0.21 (s, 61).

Example 26 (3aR,4S,9bS)- and(3aS,4R,9bR)-4-(4-hydroxy-phenyl)-2-methylene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Add KHMDS (5.7 mL of 0.5 M solution in toluene, 2.85 mmol) to a solutionof methyltriphenylphosphonium bromide (1.2 g, 3.36 nm mal) in 30 mL ofTHF at −78° C. Stir for 30 min and then add via cannula a solution ofpreparation 54 (500 mg, 0.95 mmol) in 10 mL of THF followed by 2×5 mLTHF washes. Remove cooling bath and let stir overnight. Quench withsaturated aqueous ammonium chloride. Dilute with EtOAc wash with 1:1brine:water, brine, dry over Na₂SO₄, filter and concentrate. Adsorb tosilica gel and purify by silica gel chromatography eluting with 0-100%EtOAc in hexanes to afford the title compound in addition to mono anddi-TBS protected material. Repeat the procedure starting with 250 mg ofpreparation 54 except stir for only 3 hrs. Combine the di-TBS protectedmaterial (219 mg, 0.42 mmol) and dissolve in 5 mL of THF. Add TBAF (0.88mL of a 1 M solution in THF, 0.88 mmol). Let stir for 15 min and quenchwith saturated aqueous sodium carbonate. Dilute with water and EtOAc.Separate and extract the aqueous solution with EtOAc. Combine theorganic solutions, add a little methanol, and wash with brine, dry overNa₂SO₄, filter and concentrate. Repeat the same procedure with thecombined mono-TBS protected material. Combine all the deprotectedmaterial and adsorb to 5 g of silica gel. Purify by silica gel flashchromatography eluting with 10-40% (9:1 EtOAc:MeOH) in hexanes to afford255 mg (0.87 mmol, 75%) of example 28. The two enantiomers can beseparated by chiral preparative HPLC (Chiralpak AD, MeOH). ¹H NMR (400MHz, MeOD): δ 7.32-7.29 (m, 214), 6.84-6.80 (m, 2H), 6.72 (d, J=8.8 Hz,1H), 6.64 (d, J=3.1 Hz, 1H), 6.58 (d, J=3.1, 8.8 Hz, 1H), 5.05 (d, J=1.8Hz, 1H), 4.74 (d, J=13.2 Hz, 2H), 3.54 (t, J=7.5 Hz, 1H), 2.95-2.88 (m,1H), 2.77-2.69 (m, 1H), 2.61 (d: J=16.3 Hz, 1H), 2.40-2.32 (m, 1-), 2.05(dd, J=8.8, 16.7 Hz, 1H); HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂Ofor 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.838 min; HRMS(ES−) calcd, for C₁₉H₁₇O₃: 293.1178; found: 293.1148 [M−1]. HPLC(Chiralpak AD, 15% EtOH/Heptane; 1 mL/min; t_(R)=9.0 min (enantiomer A);13.4 min (enantiomer B).

Preparation 558-(tert-Butyl-dimethyl-silanyloxy)-4-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-difluoromethylene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Dissolve diisopropylamine (67 μL, 0.48 mmol) in 2 mL of THF, cool to−50° C. and add n-butyllithium (238 μL of a 1.6 M solution in hexanes,0,38 mmol). Then add a solution of (Difluoromethyl)diphenylphosphineoxide (prepared according to Edwards, M. L.; Stemerick, D. M.; Jarvi, E.T.; Matthews, D. P.; McCarthy, J. R. Tetrahedron Lett. 1990, 31,5571-5574) in 0.5 mL of THE via cannula followed by a 0.5 mL wash. Letstir for 30 min and then add preparation 54 (100 mg, 0.19 mmol) as asolution in 0.5 mL of THE via syringe followed by a 0.5 mL wash. Letstir and allow to warm slowly to 0° C. over 2 hrs. Remove the coolingbath and let warm to room temperature and then warm to reflux for 1 hr.Cool the solution to room temperature and quench with saturated aqueousammonium chloride. Dilute the solution with EtOAc, wash with brine, dryover Na₂SO₄, filter and concentrate. Adsorb to 1 g of silica gel andpurify by silica gel chromatography eluting with 5-20% EtOAc to afford41 mg (0.073 mmol, 39%) preparation 55. ¹H NMR (400 MHz, MeOD): δ7.35-7.30 (m, 2H), 6.91-6.88 (m, 2H), 6.83 (d, J=8.3 Hz, 1H), 6.69-6.65(m, 2H), 5.14 (s, 1H), 3.60 (m, 1H), 2.82 (m, 1H), 2.74-2.64 (m, 2H),2.42 (m, 1H), 2.09 (dd, J=8.3, 15.8 Hz, 1H), 1.03 (s, 9H), 1.02 (s, 9H),0.24 (s, 6H), 0.22 (s, 6H).

Example 27 (3aR,4S,9bS)- and(3aS,4R,9bR)-2-Difluoromethylene-4-(4-hydroxy-phenyl)-1,2,3,3,a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Add TBAF (135 μL of a 1 M solution in THF, 0.135 mmol) to a solution ofpreparation 55 (38 mg, 0.068 mmol) in 1 mL of THF, Let stir for 5 min,add one more drop of TBAF and then quench with aqueous sodiumbicarbonate. Dilute with EtOAc, wash with water, brine, dry over Na₂SO₄,filter and concentrate. Adsorb to 0.5 g of silica gel and purify bysilica gel chromatography eluting with 5-50% (9:1 EtOAc:MeOH) in hexanesto afford 20 mg (0.061 mmol, 89%) of example 29. ¹H NMR (400 MHz, MeOD):δ 7.31 (m, 2H), 6.83 (m, 2H), 6.74 (d. J=8.8 Hz, 1H), 6.67 (d, J=2.6 Hz,1H), 6.61 (dd, J=2.6, 8.8 Hz, 1H), 5.07 (s, 1H), 3.60 (m, 1H), 2.86-2,73(m, 2H), 2.64 (d, J=15.4 Hz, 1H), 2.34 (m, 1H), 2.04 (m, 1H); HPLC(Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for5 min; 1 mL/min; t_(r) 10.094 min; HRMS (ES−) calcd. for C₁₉H₁₅F₂O₃:329.0989; found: 329.0999 [M−1].

Preparation 56 8-(tertButyl-dimethyl-silanyloxy)-4-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-trimethylsilanylethynyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Add 1 mL of dry THF to dry cerium trichloride (120 mg, 0.22 mmol,prepared from cerium trichloride heptahydrate according to cerium(III)chloride in the Encyclopedia of Reagents for Organic Synthesis, WileyInterscience), stir for 1 hr, and then cool to 0° C. In a separate flaskadd n-butyllithium (0.286 mL of a 1.6 M solution in hexanes, 0.46 mmol)to a solution of trimethylsilylacetylene (80 □L, 0.57 mmol) in 1 mL ofTHF cooled to −78° C. Add this solution to the cerium trichloride viacannula. Then add via cannula a solution of preparation 54 (120 mg, 0.22mmol) in 1 mL of THE followed by 2×0.5 mL THF washes. Let. stir for 3hrs. Prepare another solution of lithiated trimethylsilylacetylene asdescribed above and add it to the reaction flask via cannula. Let stirfor 1 hr. Quench the reaction with saturated aqueous ammonium chloride,dilute with EtOAc, separate and extract the aqueous solution with EtOAc.Combine the organic solutions and wash with water, brine, dry overNa₂SO₄, filter and concentrate.

Dissolve the material in 2 mL of CH₂Cl₂. Add DMAP (3 mg, 0.024 mmol),triethylamine (0.096 mL, 0.69 mmol), and then add methylchlorooxoacetate(0.032 mL, 0.34 mmol). Let stir for 1 hr. Quench with saturated sodiumbicarbonate and separate. Wash the organic solution with 1 M aqueousNaH₂PO₄, saturated aqueous sodium bicarbonate, brine, dry over Na₂SO₄,filter and concentrate. Adsorb to 1 g of silica gel and purify by silicagel flash chromatography eluting with 0-15% EtOAc in hexanes.

Dissolve the material in 1.5 mL of toluene. Add triphenyltin hydride(163 μg, 0.464 mmol) and AIBN (4 mg, 0.024 mmol). Warm the solution to80° C. Let stir for 1 hr. Remove heat and let sit for 3 hrs. Filterthrough a glass frit and wash precipitate with ether. Combine thefiltrates and concentrate. Adsorb to 1.2 g of silica gel and purify bysilica gel chromatography eluting with 0-50% CH₂Cl₂ in hexanes to afford56 mg (0.092 mmol) of preparation 56 as a 5:1 diastereomeric mixture ofproducts. ¹H NMR (400 MHz, CDCl₃) of major diastereomer: δ 7.37-7.27 (m,2H), 6.89-6.85 (m, 21), 6.81 (d, J=8.4 Hz, 1H), 6.65-6.60 (m, 2H), 4.98(d, J=2.2 Hz, 1H), 3.49 (m, 1H), 2.75-250 (m, 3H), 1.81-1.66 (m, 3H),1.03 (s, 9H), 1.02 (s, 9H), 0.24 (s, 6H), 0.22 (s, 614), 0.10 (s, 9H).

Example 28 (3aR,4S,9bS)- and(3aS,4R,9bR)-2-Ethynyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Add TBAF (0.28 mL of a 1 M solution in THF, 0.28 mmol) to a solution ofpreparation 56 (56 rug, 0.092 mmol) in 2 mL of THF. Let stir for 10 min.Quench with saturate sodium bicarbonate and dilute with EtOAc. Separateand wash the organic solution with water, brine, dry over Na₂SO₄, filterand concentrate. Adsorb to 0.5 g silica gel. Purify by silica gelchromatography elating with 0-50% (9:1 EtOAc:MeOH) in hexanes to afford11.3 mg (0.037 mmol) of example 30 as a 5:1 mixture of diastereomers. ¹HNMR (400 MHz, MeOD) of major diastereomer: δ 7.27 (m, 2H), 6.83-6.81 (m,2H), 6.74 (d, J=8.0 Hz, 1H), 6.64-6.56 (m, 2H), 4.89 (d, J=3.1 Hz, 1H),3.48 (dt, J=8.8, 5.7 Hz, 1H), 2.74-2.57 (m, 3H), 2.22 (d, J=2.6 Hz),1.64-1.57 (m, 3H); HPLC (Zorbax C18 column; 10 to 100% CH₃CN/HO for 10min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 9.683 min (major), 9.805(minor); HRMS(ES−) calcd. for C₂₀H₁₇O₃: 305.1178; found: 305.1170 [M−1].

Preparation 578-Benzyloxy-4-(4-benzyloxy-phenyl)-2-ethylidene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Heat a solution of preparation 50, (0.1562 g, 0.3278 mmol) in dry THF (6mL) to dissolve. Cool a solution of ethyltriphenylphosphonium bromide(0.49 g. 1.3 mmol) in dry THF (10 mL) to −78° C. and then add KHMDS (2.2mL of a 0.5 M solution in toluene, 1.1 mmol). After stirring at −78° C.for 15 min, add the solution of preparation 50 dropwise via cannula.Allow the solution to warm to RT for 2 h, then quench with saturatedaqueous ammonium chloride (25 mL) and water (25 mL) and extract withEtOAc (3×50 mL). Wash the combined organic solutions with brine (50 mL),dry over Na₂SO₄, filter and concentrate. Purify by silica gel flashchromatography eluting with 0-50% CH₂Cl₂ in hexanes to afford 0.1552 g(0.3179 mmol, 97%) of preparation 57 as mixture of E and Z isomers. ¹HNMR (400 MHz, CDCl₃): δ 7.36-7.50 (m, 12H, 2 isomers), 7.02-7.06 (m, 2H,2 isomers), 6.78-6.89 (m, 1H, 2 isomers), 5.22 (m, 1H, 2 isomers), 5.17(d, 1H, J=1.8 Hz, 1 isomer), 5.15 (d, 1H, J=1.3 Hz, 1 isomer), 5.13 (s,2H, 1 isomer), 5.12 (s, 2H, 1 isomer), 5.06 (s, 2H, 1 isomer), 5.05 (s,2H, 1 isomer), 3.63 (t, 1H, J=7.9 Hz, 1 isomer), 3.54 (t, 1H, J=7.0 Hz,1 isomer), 2.60-2,85 (m, 3H, 2 isomers), 2.41-2.48 (m, 1H, 1 isomer),2.25-2,32 (m, 1H, 1 isomer), 2.03-2.12 (m, 1H, 2 isomers), 1.52 (d, 3H,J=6.6 Hz, I isomer), 1.47 (d, 3H, J=7.0 Hz, 1 isomer). HRMS (CI+) calcd,for C₃₄H₃₃O₃: 489.6241; found: 489.2411 (M+1).

Preparation 588-Benzyloxy-4-(4-benzyloxy-phenyl)-2-propylidene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Preparation 58 can be prepared in a manner substantially similar topreparation 57 starting with preparation 50 (0.2041 g, 0.4283 mmol) andpropyltriphenyl-phosphonium bromide to obtain 0.1927 g (0,3 834 mmol,90%) of a mixture of E and 2 isomers. ¹H NMR (400 MHz, CDCl₃): δ7.36-7.50 (m, 12H, 2 isomers), 7.02-7,06 (m, 2H, 2 isomers), 6.79-6.89(m, 4H, 2 isomers), 5.16 (m, 1H, 1 isomer), 5.145 (m, 1H, 1 isomer),5.13 (s, 2H, 1 isomer), 5.12 (s, 2H, 1 isomer), 5,06 (s, 2H, 1 isomer),5.05 (s, 2H, 1 isomer), 3.62 (t, 1H, J=7.5 Hz), 3.54 (t, 1H, J=7.0 Hz, Iisomer), 2.58-2.92 (m, 3H, 2 isomers), 2.41-2.48 (m, 1H, 1 isomer),2.25-2.32 (m, 1 isomer), 1.85-2.11 (m, 3H, 2 isomer), 0.896 (t, 3H,J=7.5 Hz, 1-isomer), 0.863 (t, 3H, J=7.5 Hz, 1 isomer). HRMS (CI+)calcd. for C₃₃H₃₅O₃: 503.2586; found: 503.2563 (M+1).

Preparation 598-Benzyloxy-4-(4-benzyloxy-phenyl)-2-butylidene-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Preparation 59 can be prepared in a manner substantially similar topreparation 57 starting with preparation 50 (0.203 g, 0.427 mmol) andbutyltriphenyl-phosphonium to obtain (0.1894 g, 0.3665 mmol, 86%) of amixture of E and Z isomers. ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.50 (m,12H, 2 isomers), 7.02-7.06 (m, 2H, 2 isomers), 6.78-6.88 (m, 4H, 2isomers), 5.14-5.17 (m, 2H, 2 isomers), 5.13 (s, 2H, isomer), 5.12 (s,2H, 1 isomer), 5.06 (s, 2H, 1 isomer), 5.05 (s, 2H, 1 isomer), 3.61 (t,1H, J=7.5 Hz, 1 isomer), 3.54 (t, 1H, J=6.6 Hz), 2.59-2.86 (m, 3H, 2isomers), 2.42-2.49 (m, 1H, 1 isomer), 2.24-2.31 (m, 1H, 1 isomer),2.03-2.11 (m, 1H, 2 isomers), 1.80-1.89 (m, 2H, 2 isomers), 1.22-1.35(m, 2H, 2 isomers), 0.856 (t, 3H, J=7.5 Hz, 1 isomer), 0.804 (t, 31,J=7.0 Hz, 1 isomer).

Preparation 60 2-Benzylidene-8-benzyloxy-4-(4-benzyloxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene

Preparation 60 can be prepared in a manner substantially similar topreparation 57 except the reaction mixture was heated to refluxovernight. Starting with preparation 50 (0.203 g, 0.427 mmol) using twoaddition of the Wittig reagent formed from benzyltriphenyl-phosphoniumchloride affords 0.0922 g (0.167 mmol, 39%) of a mixture of E and Zisomers. ¹H NMR (400 MHz, CDCl₁): δ, 7.20-7.51 (m, 17H, 2 isomers), 7.06(d, 2H, J=8.6 Hz, 2 isomers), 6.82-6.90 (m, 4H, 2 isomers), 6.26 (s, 1H,major isomer), 5.20 (s, 1H, minor isomer), 5.18 (s, 2H, minor isomer),5.14 (s, 2H, major isomer), 5.06 (s, 2H, minor isomer), 5,03 (s, 2H,major isomer), 3.70-3.78 (m, 1H, major isomer), 3.56-3.64 (m, 1H, minorisomer), 3.12-3.25 (m, 1H, 2 isomers), 2.24-3.00 (m, 3H, 2 isomers).

Example 29 2-Butyl-4-(4-hydroxy.phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Dissolve preparation 59 (0.1829 g, 0.3540 mmol) in 11 mL of THF. Add aslurry of 10% Pd/C (0.0619 g) in 11 mL, of isopropyl alcohol. Stir thesolution under an atmosphere of hydrogen at ambient pressure andtemperature, overnight. Filter the solution through Celite and wash thefilter cake with isopropyl alcohol and THF, Combine and concentrate thefiltrate and washings and concentrate. Adsorb to 2g of silica gel.Purify by silica gel flash chromatography eluting with 10-50% (1:9MeOH/EtOAc) in hexanes to afford 0.0823 g (0.2432 mmol, 69%) of example31. ¹H NMR (400 MHz, MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d, 21, J=8.4Hz), 6.71 (d, 1H, J=8.4 Hz), 6.58 (d, 1H, J=3.1 Hz), 6.54 (dd, 1H, J=3.1Hz, J=8.8 Hz), 3.41-3.47 (m, 1H), 2.48-2.63 (m, 2H), 1.77-1.90 (m, 1-1),1.40-1.46 (m, 1H), 1.14-1.26 (m, 8H), 0.863 (t, 3H, J=6.6 Hz). HPLC(Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for5 min; 1 mL/min; t_(r) 11.575 min). LRMS (ES−): 337.2 (M−1).

The two enantiomers can be separated by chiral preparative IHPLC(Chiralpak AD, % EtOH/Heptane).

Enantiomer A: ¹H NMR (400 MHz, MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.4 Hz), 6,71 (d, 1H, J=8.4 Hz), 6.58 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz, J=8.8 Hz), 3.41-3.47 (m, 1H), 2.48-2.63 (m, 2H), 1.77-1.90(m, 1H), 1.40-1.46 (m, 1H), 1.14-1.26 (m, 8H), 0.863 (t, 3H, J=6.6 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min 1 mL/min; t_(r) 11.568 min). HPLC (Chiralpak AD, 15%EtOH/Heptane: 1 mL/min, t_(R)=3.213 min). LRMS (ES−): 337.2 (M−1).

Enantiomer B: ¹H NMR (400 MHz, MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.4 Hz), 6.71 (d, 1H, J=8.4 Hz), 6.58 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz. J=8.8 Hz), 3.41-3.47 (m, 1H), 2.48-2.63 (m, 2H), 1.77-1.90(m, 1H), 1.40-1.46 (m, 1H), 1.14-1.26 (m, ), 0.863 (t, 3H, J=6.6 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min; 1 mL/min; t_(r) 11.578 min). HPLC (Chiralpak AD, 15%EtOH/Heptane; 1 mL/min; t_(R)=5.877 min). LRMS (ES−): 337.2 (M−1).

Example 304-(4-Hydroxy-phenyl)-2-propyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

example 32 can be prepared in a manner substantially similar to thatdescribed for example 31 starting from preparation 58 (0.1842 g, 0.3665mmol) to afford 0.108 g (0.331 mmol, 90%). ¹H NMR (400 MHz, MeOD): δ7.27 (d, 2H, J=8.8 Hz), 6.81 (d, 2H, J=8.8 Hz), 6.71 (d, 1H, J=8.8H),6.58 (d, 1H, J=3.1 Hz), 6.54 (dd, 1, J=3.1 Hz, J=8.8 Hz), 3.41-3.47 (m,1H), 2.48-2.63 (m, 2H), 1.80-1.92 (m, 1H), 1.38-1.46 (m, 1H), 1.14-1.30(m, 6H), 0.849 (t, 3H, J=7.0 Hz). HPLC (Zorbax C18 column; 10 to 100%CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mL/min; t_(r) 11.137min). LRMS (ES−): 323.2 (M−1).

The two enantiomers can be separated by chiral preparative HPLC(Chiralpak AD, IPA/Heptane).

Enantiomer A: ¹H NMR (400 MHz, MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.8 Hz), 6.71 (d, 1H, J=8.8 Hz), 6.58 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz, J=−8.8 Hz), 3.41-3.47 (m, 1H), 2.48-2.63 (min, 2H),1.80-1.92 (m, 1H) 1.38-1.46 (m, 1H), 1.14-1,30 (m, 6H), 0.849 (t, 3H,J=7.0 Hz). HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then100% CH₃CN for 5 min; 1 mL/min; t_(r) 11.125 min). HPLC (Chiralpak AD,15% EtOH/Heptane; 1 mL/min; t_(R)=3.477 min). LRMS (ES−): 323.2 (M−1).

Enantiomer B: ¹H NMR (400 MHz, MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.8 Hz), 6.71 (d, 1H, J=8.8 Hz), 6.58 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz, J=8.8 Hz), 3.41-3.47 (m, 1H), 2.48-2.63 (m, 2H), 1.80-1.92(m, 1H), 1.38-1.46 (m, 1H), 1.14-0.30 (min, 6H), 0.849 t, 3H, J=7.0 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min; 1 ml/min; t_(r) 11.127 ml) HPLC (Chiralpak AD, 15% EtOHHeptane; 1 mL/min; t_(r)=6.997 min). LRMS (ES−): 323.2 (M-I).

Example 312-Ethyl-4-(4-hydroxy-phenyl)-1,2,3,3a-4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Example 33 can be prepared in a manner substantially similar to thatdescribed for example 31 starting from preparation 57. ¹H NMR (400 MHz,MeOD): δ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d, 2H, J=8.4 Hz), 6.71 (d, 1H,J=8.8 Hz), 6.59 (d, 1H, J=3.1 Hz), 6.54 (dd, 1H, J=3.1 Hz, J=8.8 Hz),3.42-3.48 (m, 1H), 2.49-2.63 (m, 2H), 1.71-1.83 (m, 1H), 140-1.47 (m,1H), 1.15-1.26 (m, 4H), 0.829 (t, 3H, J=7.5 Hz). HPLC (Zorbax C18column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for 5 min; 1 mLmin; t_(r) 10.681 min) LRMS (ES−): 309.2 (M−1).

The two enantiomers can be separated by chiral preparative HPLC(Chiralpak AD, % EtOH/Heptane).

Enantiomer A: ¹H NMR (400 MHz, MeOD): □ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.4 Hz), 6,71 (d, 1H, J=8.8 Hz), 6.59 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz, J=8.8 Hz), 3.42-3.48 (m, 1H), 2.49-2.63 (m, 2H), 1.71-1.83(m, 1H), 1.40-1.47 (m, 1H), 1.15-1.26 (m, 4H), 0.829 (t., 31, J=7.5 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN I H2, for 10 min then 100%CH₃CN for 5 min; 1 mL/min; t_(r) 10.703 min). HPLC (Chiralpak AD, 15%EtOH/Heptane; 1 mL/min; t_(R)=3.687 min). LRMS (ES−) 309.2.

Enantiomer B: ¹H NMR (400 MHz, MeOD): □ 7.27 (d, 2H, J=8.8 Hz), 6.81 (d,2H, J=8.4 Hz), 6.71 (d, 1H, J=8.8 Hz), 6.59 (d, 1H, J=3.1 Hz), 6.54 (dd,1H, J=3.1 Hz, J=8.8 Hz), 3.42-3.48 (m, 1H), 2.49-2.63 (m, 2H), 1.71-1.83(m, 1H), 1.40-1.47 (m, 1H), 1.15-1.26 (m, 4H), 0.829 (t, 3H, J=7.5 Hz).HPLC (Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CNfor 5 min; 1 mL/min; t_(r) 10.663 min). HPLC (Chiralpak AD, 15%EtOH/Heptane; 1 mL/min; t_(R)=8.264 min). LRMS (ES−) 309.2 (M−1).

Example 322-Benzyl-4-(4-hydroxy-phenyl)-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol

Example 34 can be prepared in a manner substantially similar to thatdescribed for example 31 starting from preparation 60 except under anatmosphere of hydrogen at 60 psi of Ha. ¹H NMR (400 MHz, MeOD): □ 7.05(m, 7H), 6.79 (d, 2H, J=8.8 Hz), 6.74 (d, 1H, J=8.4 Hz), 6.56-6.58 (m,2H), 4.90-4.92 (m, 1H), 3.40-3.46 (m, 1H), 2.58-2.66 (m, 1H), 2.46-2.56(m, 1H), 2.32-2.43 (m, 2H), 2.10-2.22 (m, 1H), 1.28-1.45 (m, 3H). HPLC(Zorbax C18 column; 10 to 100% CH₃CN/H₂O for 10 min then 100% CH₃CN for5 min; 1 mL/min; t_(r) 11.269 rain). LRMS (ES−): 371.2 (M−1).

Test Procedures ER Binding Assay

The competition ER binding assay was nm in a buffer containing 50 mMN-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid (Hepes) pH 7.5,1.5 mM EDTA, 150 mM NaCl, 10% glycerol, 1 mg/mL ovalbumin, 5 mM DTT,0.025 μCi per well of ³H-Estradiol(NEN #NET517 at 118 Ci/mmol, 1mCi/mL), and 10 ng/well ERAlpha or ERbeta Receptor (PanVera). Competingcompounds were added at 10 different concentrations. Non-.specificbinding was determined in the presence of 1 μM of E2 (17-β Estradiol,Sigma, St. Louis, Mo.). The binding reaction (140 μL) was incubated for4 hours at room temperature, then 70 μL of cold dextran coated charcoal(DCC) buffer was added to each reaction (DCC buffer was prepared byadding 0.75 g of charcoal [Sigma] and 0.25 g of dextran [Pharmacia]per50 mL of assay buffer). The incubation plates were mixed for 8 minuteson an orbital shaker at 4° C. and then centrifuged at 3,000 rpm for 10minutes at 4° C. An aliquot of 120 μl of the mix was transferred toanother 96-well, white flat bottom plate (Costar) and 175 μl of WallacOptiphase Hisafe 3 scintillation fluid was added to each well. Theplates were sealed and then shaken vigorously on an orbital shaker.After an incubation of 2.5 hrs, the radioactivity was counted in aWallac Microbeta counter. The IC₅₀ and percent inhibition at 10 μM werecalculated. The K_(d) for ³H-Estradiol was determined by saturationbinding to ERα and ERβ receptors. The IC₅₀ values for compounds wereconverted to K_(i) values using the Cheng-Prusoff equation and the K_(d)values were determined by saturation binding assay. Compounds ofExamples 1-19 and 22-25 are active in the assay as described. Preferredcompounds bind to the ER beta receptor with a K_(i) of less than 20 nM.More preferred compounds bind to the ER beta receptor with a K_(i) ofless than 1 nM. Compounds that are selective to binding to the ER betareceptor compared to the ER alpha receptor bind to the ER beta receptorwith a lower K_(i) compared to the K_(i) for the ER alpha receptor.

As determined by the above assay, the compounds of examples 1-32 exhibitbinding affinities (Kis) at the ER Alpha subtype in the range5.0->10,000 nM and to the ER beta subtype in the range of 0.20-429 nM.

LNCaP Human PCa Xenograft Assay

ERbeta agonists are evaluated for their effects on the growth ofandrogen-sensitive LNCaP human prostatic cancer (PCa) xenografts grownin intact sexually mature (5-6 weeks old) Hsd: Athymic Nude-nu (AthymicNude) male mice. 2.0×10⁶ LNCaP tumor cells are injected bilaterally bythe subcutaneous route into the pre-tracheal region of testicular intactmale mice. Mice are castrated via the scrotal route to serve as thepositive control group. Test compounds are administered once per day bysubcutaneous or gavage administration at multiple dose levels in avolume of 0.2 ml to xenograft-bearing mice starting on the day followingtumor injection. Test compounds are reformulated weekly based on averagegroup mean body weights. The vehicle for these studies is 1%carboxymethyl cellulose (CMC) with 0.25% Tween 80. Body weights andtumor measurements are recorded on a weekly basis and entered directlyinto a JMP™ (SAS; Cary, N.C.) spreadsheet from electronic calipermeasurement, Tumor volumes in mm³ are calculated in JMP using thefollowing formula: L×W×H×0.5236. Tumor and body weight responses forindividual mice are recorded on a weekly basis. When LNCaP tumor volumesenter log-phase expansion, lesions are measured every 3-4 days. Growthrates are determined using linear modeling of the log tumor values andtime to treatment failure (tumor vol=1300-1500 mm³) are determined usinga linear extrapolation model (SAS; Cary, N.C.). Because of humane animaluse considerations, animals are sacrificed when their tumor volumesapproach 1200-1400 mm³. At necropsy, final tumor measurement and bodyweights are recorded and whole blood is obtained via cardiac punctureand allowed to clot on ice. Serum is transferred to appropriatelylabeled 0.5 ml Eppendorf micro tubes, and samples are stored at −80° C.for biomarker analysis.

General Rat Preparation Procedure

Seventy-five day old (unless otherwise indicated) female Sprague Dawleyrats (weight range of 200 to 225g) are obtained from Charles RiverLaboratories (Portage, Mich.). The animals are either bilaterallyovariectomized (OVX) or exposed to a Sham surgical procedure at CharlesRiver Laboratories, and then shipped after one week. Upon arrival, theyare housed in metal hanging cages in groups of 3 or 4 per cage and havead libitum access to food (calcium content approximately 0.5%) and waterfor one week. Room temperature is maintained at 22.2°±1.7° C. with aminimum relative humidity of 40%. The photoperiod in the room was 12hours light and 12 hours dark.

Dosing Regimen Tissue Collection: After a one week acclimation period(therefore, two weeks post-OVX) daily dosing with a compound of formula(I) (“F-I”) is initiated. 17α-ethynyl estradiol or F-I is given orally,unless otherwise stated, as a suspension in 1% carboxymethylcellulose ordissolved in 20% cyclodextrin. Animals are dosed daily for 4 days.Following the dosing regimen, animals are weighed and anesthetized witha ketamine: Xylazine (2:1, v:v) mixture and a blood sample is collectedby cardiac puncture. The animals are then sacrificed by asphyxiationwith CO₂, the uterus is removed through a midline incision, and a wetuterine weight is determined. 17α-ethynyl estradiol is obtained fromSigma Chemical Co., St. Louis, Mo.

Cardiovascular Disease/Hyperlipidemia

The blood samples from above are allowed to clot at room temperature for2 hours, and serum is obtained following centrifugation for 10 minutesat 3000 rpm. Serum cholesterol is determined using a Boehringer MannheimDiagnostics high performance cholesterol assay. Briefly the cholesterolis oxidized to cholest-4-en-3-one and hydrogen peroxide. The hydrogenperoxide is then reacted with phenol and 4-aminophenazone in thepresence of peroxidase to produce a p-quinone imine dye, which is readspectrophotemetrically at 500 mm. Cholesterol concentration is thencalculated against a standard curve. The entire assay is automated usinga Biorek Automated Workstation.

Uterine Eosinophil Peroxidase (EPO) Assay

The uteri from above are kept at 4° C. until time of enzymatic analysis.The uteri are then homogenized in 50 volumes of 50 mMI Tris buffer (pH8.0) containing 0.005% Triton X-100. Upon addition of 0.01% hydrogenperoxide and 10 mM O-phenylenediamine (final concentrations) in Trisbuffer, increase in absorbance is monitored for one minute at 450 um.The presence of eosinophils in the uterus is an indication of estrogenicactivity of a compound. The maximal velocity of a 15 second interval isdetermined over the initial, linear portion of the reaction curve.

Inhibition of Bone Loss (Osteoporosis) Test Procedure

Following the general preparation procedure described above, the ratsare treated daily for thirty-five days (6 rats per treatment group) andsacrificed by carbon dioxide asphyxiation on the 36th day. Thethirty-five day time period is sufficient to allow maximal reduction inbone density, measured as described herein. At the time of sacrifice,the uteri are removed, dissected free of extraneous tissue, and thefluid contents are expelled before determination of wet weight in orderto confirm estrogen deficiency associated with complete ovariectomy.Uterine weight is routinely reduced about 75% in response toovariectomy. The uteri are then placed in 10% neutral buffered formalinto allow for subsequent histological analysis.

The right femurs are excised and digitilized X-rays generated andanalyzed by an image analysis program (NIH image) at the distalmetaphysis. The proximal aspect of the tibiae from these animals arealso scanned by quantitative computed tomography. In accordance with theabove procedures, F-1 or ethynyl estradiol (EE₂) in 20% hydroxypropylβ-cyclodextrin are orally administered to test animals.

Therapeutic Methods of Use and Dosages

Various diseases and conditions described to be treated herein, are wellk own and appreciated by those skilled in the art. It is also recognizedthat one skilled in the art may affect the associated diseases andconditions by treating a patient presently afflicted with the diseasesor conditions or by prophylactically treating a patient afflicted withthe diseases or conditions with a therapeutically effective amount ofthe compounds of formula (I).

As used herein, the term “patient” refers to a warm blooded animal suchas a mammal that is afflicted with a particular estrogen receptor-betamediated disease. It is understood that guinea pigs, dogs, cats, rats,mice, horses, cattle, sheep, and humans are examples of animals withinthe scope of the meaning of the term.

As used herein. the term “therapeutically effective amount” of acompound of formula (I) refers to an amount which is effective incontrolling diseases and conditions associated with estrogenreceptor-beta mediated diseases such as prostate cancer, benignprostatic hyperplasia, testicular cancer, cardiovascular diseases,neurodegenerative disorders, urinary incontinence, CNS disorders, GItract disorders, and osteoporosis. The term “controlling” is intended torefer to all processes wherein there may be a slowing, interrupting,arresting, or stopping of the progression of the diseases and conditionsdescribed herein, but does not necessarily indicate a total eliminationof all disease and condition symptoms, but does include prophylactictreatment of the diseases and conditions associated with estrogenreceptor-beta mediated diseases such as prostate cancer, benignprostatic hyperplasia, testicular cancer, cardiovascular diseases,neurodegenerative disorders, urinary incontinence, CNS, GI tractdisorders, and osteoporosis.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, the dose, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the specific disease involved; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

A therapeutically effective amount of a compound of formula (I) isexpected to vary from about 0.001 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts can bedetermined by one skilled in the art.

In effecting treatment of a patient afflicted with the diseases andconditions described above, a compound of formula (I) can beadministered in any form or mode which makes the compound bioavailablein a therapeutically effective amount, including oral, inhalation, andparenteral routes, For example, compounds of formula (I) can beadministered orally, by inhalation of an aerosol or dry powder,subcutaneously, intramuscularly, intravenously, transdermally,intranasally, rectally, topically, and the like. Oral or inhalationadministration is generally preferred for treatment of respiratorydiseases, e.g. asthma. One skilled in the art of preparing formulationscan readily select the proper form and mode of administration dependingupon the particular characteristics of the compound selected, thedisease or condition state to be treated, the stage of the disease orcondition, and other relevant circumstances. (Remington's PharmaceuticalSciences, 18th Edition, Mack Publishing Co. (1990)).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts,such as acid addition salts or base addition salts, for purposes ofstability, convenience of crystallization, increased solubility and thelike.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (I) in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material, which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solution, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the compound of the presentinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit The amount of the compound present in compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention may be determined bysomeone skilled in the art.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring, When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials that modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain. preservatives,dyes and colorings and flavors. Materials used in preparing thesevarious compositions should be pharmaceutically pure and non-toxic inthe amounts used.

For the purpose of parenteral therapeutic administration, the compoundsbf the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the compound of formula (I)present in such compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations are able to bedetermined by one skilled in the art.

The compounds of the present invention may also be administered byinhalation, such as by aerosol or dry powder. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe compounds of the present invention or a formulation thereof.Formulations for administration by inhalation of compounds of formula(I) may be delivered in single phase, bi-phasic, or tri-phasic systems.A variety of systems are available for the administration by aerosols ofthe compounds of formula (I). Dry powder formulations are prepared byeither pelletizing or milling the compound of formula (I) to a suitableparticle size or by admixing the pelletized or milled compound offormula (I) with a suitable carrier material, such as lactose and thelike. Delivery by inhalation includes the necessary container,activators, valves, subcontainers, and the like. Preferred aerosols anddry powder formulations for administration by inhalation are able to bedetermined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, ointment or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols, beewax, mineral oil, diluents such as water and alcohol, and emulsifiersand stabilizers. Topical formulations may contain a concentration of theformula (I) or its pharmaceutical salt from about 0.1 to about 10% w/v(weight per unit volume).

The solutions or suspensions may also include one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerin, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

1. (canceled)
 2. A compound according to the formula:

wherein O, S(O)n, wherein n is 0-2; or a pharmaceutically acceptablesalt thereof.
 3. A compound selected from: e)(3aS,4S,9bS)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol;f)(3aR,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-2,5dioxa-cyclopenta[a]naphthalen-8-ol;g)(3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol;h)(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol;i)(2S,3aR,4S,9bS)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cyclopenta[a]naphthalen-8-ol;j)(2R,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁴-thia-cyclopenta[a]naphthalen-8-ol;k)(3aR,4S,9bR)-4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ⁶-thia-cyclopenta[a]naphthalen-8-ol;(3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2,2-dioxo-1,2,3,3a,4,9b-hexahydro-5-oxta-2λ⁶-thia-cyclopenta[a]naphthalen-8-ol;for a pharmaceutically acceptable salt thereof.
 4. (canceled) 5.(canceled)
 6. (canceled)
 7. A compound according to claim 2 wherein thecompound is of the formula:

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 2 wherein the compound is of the formula:

of or a pharmaceutically acceptable salt thereof.
 9. A compoundaccording to claim 2 wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 2 wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof. 11-37. (canceled)
 38. Apharmaceutical composition comprising a compound of claim 2 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier. 39-44. (canceled)